bims-rehoca Biomed News
on Redox homeostasis in cancer
Issue of 2021‒10‒03
forty-seven papers selected by
Vittoria Raimondi
Veneto Institute of Oncology
  1. Effect of Exogenous pH on Cell Growth of Breast Cancer Cells.
  2. Antioxidants Threaten Multikinase Inhibitor Efficacy against Liver Cancer by Blocking Mitochondrial Reactive Oxygen Species.
  3. Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells.
  4. Time-programmed activation of dual polyprodrugs for synergistic cascade oxidation-chemotherapy.
  5. Nepenthes Extract Induces Selective Killing, Necrosis, and Apoptosis in Oral Cancer Cells.
  6. Synthesis and biological evaluation of NO-donor containing photosensitizers to induce ferroptosis of cancer cells.
  7. Synergistic Cotreatment Potential of Soursop (Annona muricata L.) Leaves Extract with Doxorubicin on 4T1 Cells with Antisenescence and Anti-reactive-oxygen-species Properties.
  8. CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated p38/CHOP/death receptor 5 signaling pathways.
  9. Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway.
  10. Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy.
  11. Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction.
  12. Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells.
  13. NIR-triggerable ROS-responsive cluster-bomb-like nanoplatform for enhanced tumor penetration, phototherapy efficiency and antitumor immunity.
  14. Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells.
  15. Exploring Hyperoxia Effects in Cancer-From Perioperative Clinical Data to Potential Molecular Mechanisms.
  16. Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress.
  17. Induction of mitochondria mediated apoptosis in human ovarian cancer cells by folic acid coated tin oxide nanoparticles.
  18. SLC7A11/ xCT is a target of miR-5096 and its restoration partially rescues miR-5096-mediated ferroptosis and anti-tumor effects in human breast cancer cells.
  19. Sesamol induces cytotoxicity via mitochondrial apoptosis in SCC-25 cells.
  20. A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy.
  21. Synergistic effect of anethole and doxorubicin alleviates cell proliferation, cell cycle arrest, and ER stress and promotes ROS-mediated apoptosis in triple-negative breast cancer cells.
  22. Nepenthes Ethyl Acetate Extract Provides Oxidative Stress-Dependent Anti-Leukemia Effects.
  23. Receptor based virtual screening of potential novel inhibitors of tigar [TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator.
  24. PRODH/POX-Dependent Celecoxib-Induced Apoptosis in MCF-7 Breast Cancer.
  25. Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia.
  26. Oxidative Stress and Multi-Organel Damage Induced by Two Novel Phytocannabinoids, CBDB and CBDP, in Breast Cancer Cells.
  27. Simulated microgravity triggers DNA damage and mitochondria-mediated apoptosis through ROS generation in human promyelocytic leukemic cells.
  28. A Novel Approach to Unraveling the Apoptotic Potential of Rutin (Bioflavonoid) via Targeting Jab1 in Cervical Cancer Cells.
  29. Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled.
  30. Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma.
  31. The Novel Antioxidant Compound JSH-23 Prevents Osteolysis by Scavenging ROS During Both Osteoclastogenesis and Osteoblastogenesis.
  32. Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy.
  33. Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis.
  34. Soft X-Ray Stimulated Lanthanide@MOF Nanoprobe for Amplifying Deep Tissue Synergistic Photodynamic and Antitumor Immunotherapy.
  35. Dark Side of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, and Immune Modulation.
  36. Hydroxychloroquine Induces Apoptosis in Cholangiocarcinoma via Reactive Oxygen Species Accumulation Induced by Autophagy Inhibition.
  37. Redox-Sensitive and Folate-Receptor-Mediated Targeting of Cervical Cancer Cells for Photodynamic Therapy Using Nanophotosensitizers Composed of Chlorin e6-Conjugated β-Cyclodextrin via Diselenide Linkage.
  38. The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer.
  39. Therapeutic ROS and Immunity in Cancer-The TRIC-21 Meeting.
  40. MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia.
  41. SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism.
  42. Betulinic Acid-Doxorubicin-Drug Combination Induced Apoptotic Death via ROS Stimulation in a Relapsed AML MOLM-13 Cell Model.
  43. The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival.
  44. Proteomics analysis reveals the correlation of programmed ROS-autophagy loop and dysregulated G1/S checkpoint with imatinib resistance in Chronic Myeloid Leukemia cells.
  45. Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.
  46. Molecular Design of Monochromophore-Based Bifunctional Photosensitizers for Simultaneous Ratiometric Oxygen Reporting and Photodynamic Cancer Therapy.
  47. 7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway.
  1. Int J Mol Sci. 2021 Sep 14. pii: 9910. [Epub ahead of print]22(18):
    Effect of Exogenous pH on Cell Growth of Breast Cancer Cells.
    Sungmun Lee, Aya Shanti.
      Breast cancer is the most common type of cancer in women and the most life-threatening cancer in females worldwide. One key feature of cancer cells, including breast cancer cells, is a reversed pH gradient which causes the extracellular pH of cancer cells to be more acidic than that of normal cells. Growing literature suggests that alkaline therapy could reverse the pH gradient back to normal and treat the cancer; however, evidence remains inconclusive. In this study, we investigated how different exogenous pH levels affected the growth, survival, intracellular reactive oxygen species (ROS) levels and cell cycle of triple-negative breast cancer cells from MDA-MB-231 cancer cell lines. Our results demonstrated that extreme acidic conditions (pH 6.0) and moderate to extreme basic conditions (pH 8.4 and pH 9.2) retarded cellular growth, induced cell death via necrosis and apoptosis, increased ROS levels, and shifted the cell cycle away from the G0/G1 phase. However, slightly acidic conditions (pH 6.7) increased cellular growth, decreased ROS levels, did not cause significant cell death and shifted the cell cycle from the G0/G1 phase to the G2/M phase, thereby explaining why cancer cells favored acidic conditions over neutral ones. Interestingly, our results also showed that cellular pH history did not significantly affect the subsequent growth of cells when the pH of the medium was changed. Based on these results, we suggest that controlling or maintaining an unfavorable pH (such as a slightly alkaline pH) for cancer cells in vivo could retard the growth of cancer cells or potentially treat the cancer.
    Keywords:  apoptosis; breast cancer; cell cycle; exogenous pH; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms22189910
  2. Antioxidants (Basel). 2021 Aug 24. pii: 1336. [Epub ahead of print]10(9):
    Antioxidants Threaten Multikinase Inhibitor Efficacy against Liver Cancer by Blocking Mitochondrial Reactive Oxygen Species.
    Blanca Cucarull, Anna Tutusaus, Tania Hernáez-Alsina, Pablo García de Frutos, María Reig, Anna Colell, Montserrat Marí, Albert Morales.
      Sorafenib and regorafenib, multikinase inhibitors (MKIs) used as standard chemotherapeutic agents for hepatocellular carcinoma (HCC), generate reactive oxygen species (ROS) during cancer treatment. Antioxidant supplements are becoming popular additions to our diet, particularly glutathione derivatives and mitochondrial-directed compounds. To address their possible interference during HCC chemotherapy, we analyzed the effect of common antioxidants using hepatoma cell lines and tumor spheroids. In liver cancer cell lines, sorafenib and regorafenib induced mitochondrial ROS production and potent cell death after glutathione depletion. In contrast, cabozantinib only exhibited oxidative cell death in specific HCC cell lines. After sorafenib and regorafenib administration, antioxidants such as glutathione methyl ester and the superoxide scavenger MnTBAP decreased cell death and ROS production, precluding the MKI activity against hepatoma cells. Interestingly, sorafenib-induced mitochondrial damage caused PINK/Parkin-dependent mitophagy stimulation, altered by increased ROS production. Finally, in sorafenib-treated tumor spheroids, while ROS induction reduced tumor growth, antioxidant treatments favored tumor development. In conclusion, the anti-tumor activity of specific MKIs, such as regorafenib and sorafenib, is altered by the cellular redox status, suggesting that uncontrolled antioxidant intake during HCC treatment should be avoided or only endorsed to diminish chemotherapy-induced side effects, always under medical scrutiny.
    Keywords:  BCL-2; apoptosis; chemotherapy; glutathione; hepatocellular carcinoma; mitochondria; mitophagy; oxidative stress; superoxide; tumor spheroids
    DOI:  https://doi.org/10.3390/antiox10091336
  3. Front Cell Dev Biol. 2021 ;9 728172
    Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells.
    Lingyan Zhang, Jian Zhang, Yuanqing Jin, Gang Yao, Hai Zhao, Penghai Qiao, Shuguang Wu.
      Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.
    Keywords:  Nrf2; cancer; ferroptosis; iron homeostasis; redox balance
    DOI:  https://doi.org/10.3389/fcell.2021.728172
  4. Biomaterials. 2021 Sep 20. pii: S0142-9612(21)00493-2. [Epub ahead of print]278 121136
    Time-programmed activation of dual polyprodrugs for synergistic cascade oxidation-chemotherapy.
    Ye Liu, Maolin Jiang, Yalan Tu, Kewei Wang, Qingyu Zong, Youyong Yuan.
      Combination therapy using multiple drugs with time-programmed administration is promising for enhanced cancer treatment. However, it is still challenging to achieve time-programmed drug release from a single nanocarrier. Here, dual polyprodrugs of hemicyanine dye (CyNH2) and doxorubicin (DOX) are developed to achieve time-programmed prodrug activation for synergistic cascade oxidation therapy and chemotherapy. The polyprodrug NPDOX/Cy, composed of CyNH2, is modified with a glutathione (GSH)-responsive disulfate group, while DOX is modified with a reactive oxygen species (ROS)-response thioketal (TK) group. Upon uptake by cancer cells overexpressing GSH, CyNH2 can be activated quickly and accumulate in the mitochondria to induce mitochondrial damage and ROS upregulation, thus achieving subsequent burst activation of DOX through the ROS-triggered cleavage of the TK linker. The early activation of CyNH2 makes the cancer cells more sensitive to subsequent DOX treatment for a synergistic effect of from oxidation therapy and chemotherapy. Therefore, the polyprodrug with time-programmed drug activation developed in this work provides a promising strategy for synergistic cancer therapy.
    Keywords:  Oxidation-chemotherapy; Prodrug; Synergistic; Time-programmed
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121136
  5. J Pers Med. 2021 Aug 31. pii: 871. [Epub ahead of print]11(9):
    Nepenthes Extract Induces Selective Killing, Necrosis, and Apoptosis in Oral Cancer Cells.
    Kun-Han Yang, Jen-Yang Tang, Yan-Ning Chen, Ya-Ting Chuang, I-Hsuan Tsai, Chien-Chih Chiu, Li-Jie Li, Tsu-Ming Chien, Yuan-Bin Cheng, Fang-Rong Chang, Ching-Yu Yen, Hsueh-Wei Chang.
      Ethyl acetate Nepenthes extract (EANT) from Nepenthes thorellii × (ventricosa × maxima) shows antiproliferation and apoptosis but not necrosis in breast cancer cells, but this has not been investigated in oral cancer cells. In the present study, EANT shows no cytotoxicity to normal oral cells but exhibits selective killing to six oral cancer cell lines. They were suppressed by pretreatment of the antioxidant inhibitor N-acetylcysteine (NAC), demonstrating that EANT-induced cell death was mediated by oxidative stress. Concerning high sensitivity to EANT, Ca9-22 and CAL 27 oral cancer cells were chosen for exploring detailed selective killing mechanisms. EANT triggers a mixture of necrosis and apoptosis as determined by annexin V/7-aminoactinmycin D analysis. Still, they show differential switches from necrosis at a low (10 μg/mL) concentration to apoptosis at high (25 μg/mL) concentration of EANT in oral cancer cells. NAC induces necrosis but suppresses annexin V-detected apoptosis in oral cancer cells. Necrostatin 1 (NEC1), a necroptosis inhibitor, moderately suppresses necrosis but induces apoptosis at 10 μg/mL EANT. In contrast, Z-VAD-FMK, a pancaspase inhibitor, slightly causes necrosis but suppresses apoptosis at 10 μg/mL EANT. Furthermore, the flow cytometry-detected pancaspase activity is dose-responsively increased but is suppressed by NAC and ZVAD, although not for NEC1 in oral cancer cells. EANT causes several oxidative stress events such as reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization. In response to oxidative stresses, the mRNA for antioxidant signaling, such as nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), heme oxygenase 1 (HMOX1), and thioredoxin (TXN), are overexpressed in oral cancer cells. Moreover, EANT also triggers DNA damage, as detected by γH2AX and 8-oxo-2'-deoxyguanosine adducts. The dependence of oxidative stress is validated by the evidence that NAC pretreatment reverts the changes of cellular and mitochondrial stress and DNA damage. Therefore, EANT exhibits antiproliferation involving an oxidative stress-dependent necrosis/apoptosis switch and DNA damage in oral cancer cells.
    Keywords:  Nepenthes; apoptosis; necrosis; oral cancer; oxidative stress; preferential killing
    DOI:  https://doi.org/10.3390/jpm11090871
  6. Bioorg Chem. 2021 Sep 20. pii: S0045-2068(21)00732-X. [Epub ahead of print]116 105355
    Synthesis and biological evaluation of NO-donor containing photosensitizers to induce ferroptosis of cancer cells.
    Xiuhan Guo, Haoze Yu, Wanjie Shen, Rui Cai, Yueqing Li, Guangzhe Li, Weijie Zhao, Shisheng Wang.
      Photodynamic therapy (PDT) is a non-invasive treatment method for tumors by exciting photosensitizers (PS) upon light irradiation to generate cytotoxic reactive oxygen species (ROS). However, the low oxygen concentration near the tumor tissue limits the therapeutic effect of PDT. Herein, we synthesized six chlorin e6 derivatives containing NO-donors to enhance their antitumor activity by synergistic effect of ROS and NO. The results revealed that the new NO-donor containing photosensitizers (PS-NO) exhibited more potent photodynamic activity than chlorin e6, and the introduction of NO donor moieties to chlorin e6 increased the level of NO and ROS in cells. The addition of Ferrostatin-1, a ferroptosis inhibitor, markedly reduced the photodynamic activity of PS-NO as well as the level of NO and ROS in cells. Mechanism studies further showed that PS-NO could reduce intracellular GSH level, inhibit GPX4 activity and promote malondialdehyde (MDA) accumulation upon light irradiation, which suggested the ferroptosis mechanism underlying the PDT effect of PS-NO.
    Keywords:  NO donor; Photodynamic therapy; Photosensitizer; ROS; ferroptosis
    DOI:  https://doi.org/10.1016/j.bioorg.2021.105355
  7. Iran J Pharm Res. 2021 ;20(2): 57-67
    Synergistic Cotreatment Potential of Soursop (Annona muricata L.) Leaves Extract with Doxorubicin on 4T1 Cells with Antisenescence and Anti-reactive-oxygen-species Properties.
    Irfani Aura Salsabila, Nadzifa Nugraheni, Faradiba Nur Ahlina, Sari Haryanti, Edy Meiyanto.
      Annona muricata L. extract (AME) exhibits cytotoxic activities on various types of cancer cells. This study aims to unveil the anticancer activity of AME as a cotreatment agent with doxorubicin (dox) on 4T1 cells and AME's relation to senescence. AME was obtained by maceration using 96% ethanol. AME was then subjected to qualitative analysis using TLC compared to quercetin (hRf = 75). Spectrophotometry analysis of AME resulted in a total flavonoid content of 2.3% ± 0.05%. Cytotoxic evaluation using the MTT assay revealed that AME showed an IC50 value of 63 µg/mL, while its combination (25 µg/mL) with dox (10 nM) decreased the viability of 4T1 cells to 58 % (CI = 0.15). Flowcytometry using propidium iodide staining confirmed that AME (13 and 25 µg/mL) caused cell cycle arrest in the G1 phase as a single treatment and G2/M arrest in combination with dox. However, by using the dichloro dihydrofluorescein diacetate staining assay, it turned out that AME at concentrations of 13 and 25 µg/mL decreased intracellular reactive oxygen species (ROS) levels both as a single treatment and in combination with dox. Senescence-associated β - galactosidase assay showed that AME decreased dox-induced senescence. AME alone and in combination with dox (cotreatment) showed cytotoxic effect synergistically on 4T1 cells, but this was not caused by an increase in intracellular ROS levels as well as senescence induction. Therefore, AME showed its potential to be a cotreatment agent with antioxidant property on triple-negative breast cancer cells.
    Keywords:  4T1 cells; Annona muricata L.; Cytotoxic cotreatment; Doxorubicin; Reactive oxygen species; Senescence
    DOI:  https://doi.org/10.22037/ijpr.2020.112485.13788
  8. Environ Toxicol. 2021 Oct 02.
    CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated p38/CHOP/death receptor 5 signaling pathways.
    Chun-Chen Huang, Yi-Ching Cheng, Ying-Chao Lin, Chun-Hung Chou, Chi-Tang Ho, Hao-Kuang Wang, Tzong-Der Way.
      Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows little or no toxicity in most normal cells and preferentially induces apoptosis in a variety of malignant cells. However, patients develop resistance to TRAIL, therefore, sensitizing agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are necessary. In this study, we investigated the effect of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), an useful flavonoid, to overcome the TRAIL-resistant triple negative breast cancer (TNBC) cells. We found that CSC-3436 potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells and this correlated with the upregulation of death receptors (DR)-5 and down-regulation of decreased decoy receptor (DcR)-1 expression. When examined for its mechanism, we found that the decreased expression of anti-apoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, Survivin, and XIAP. CSC-3436 would increase the expression of Bax and promoted the cleavage of bid. In addition, the induction of DR5 by CSC-3436 was found to be dependent on the modulation of reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results indicated that CSC-3436 could potentiate the apoptotic effects of TRAIL through down-regulation of cell survival proteins and upregulation of DR5 via the ROS-mediated upregulation of CHOP protein.
    Keywords:  CSC-3436; ROS; TARIL; death receptor; triple negative breast cancer
    DOI:  https://doi.org/10.1002/tox.23372
  9. Open Life Sci. 2021 ;16(1): 961-968
    Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway.
    Guang-Yan Zhang, Wei-Yong Chen, Xiao-Bo Li, Hua Ke, Xue-Lin Zhou.
      Scutellarin plays an anti-tumor role in A549 lung cancer cells, but the underlying mechanism is unclear. In this study, scutellarin was used to treat A549 cells for 12, 24, and 48 h, followed by the addition of Tempo, a selective scavenger of mitochondrial reactive oxygen species (ROS) and SB431542, a transforming growth factor (TGF)-β1 receptor inhibitor. A dihydroethidium fluorescence probe was used to measure the intracellular ROS level, Cell Counting Kit-8 (CCK-8) was used to detect cell viability, and flow cytometry was performed to examine apoptosis. Western blots were used to detect the total protein level of TGF-β1, p-smad2, and cleaved caspase-3 in A549 cells. The results showed that scutellarin significantly inhibited cell viability and increased apoptosis. Scutellarin also promoted intracellular ROS production, TGF-β1/smad2 signaling pathway activation, and cleaved caspase-3 expression, which was partly reversed by Tempo. Moreover, scutellarin-induced intracellular ROS production and cleaved caspase-3 expression were inhibited by blocking the TGF-β1/smad2 pathway with SB431542. In conclusion, scutellarin promoted apoptosis and intracellular ROS accumulation, which could be abrogated by Tempo and SB431542 treatment in A549 cells. Our study indicated that scutellarin induced A549 cell apoptosis via the TGF-β1/smad2/ROS/caspase-3 pathway.
    Keywords:  A549 cells; ROS; TGF-β1/smad2; apoptosis; cleaved caspase-3; scutellarin
    DOI:  https://doi.org/10.1515/biol-2021-0085
  10. Genes (Basel). 2021 Aug 29. pii: 1348. [Epub ahead of print]12(9):
    Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy.
    Kazuo Tomita, Yoshikazu Kuwahara, Kento Igarashi, Mehryar Habibi Roudkenar, Amaneh Mohammadi Roushandeh, Akihiro Kurimasa, Tomoaki Sato.
      Mitochondria are very important intracellular organelles because they have various functions. They produce ATP, are involved in cell signaling and cell death, and are a major source of reactive oxygen species (ROS). Mitochondria have their own DNA (mtDNA) and mutation of mtDNA or change the mtDNA copy numbers leads to disease, cancer chemo/radioresistance and aging including longevity. In this review, we discuss the mtDNA mutation, mitochondrial disease, longevity, and importance of mitochondrial dysfunction in cancer first. In the later part, we particularly focus on the role in cancer resistance and the mitochondrial condition such as mtDNA copy number, mitochondrial membrane potential, ROS levels, and ATP production. We suggest a therapeutic strategy employing mitochondrial transplantation (mtTP) for treatment-resistant cancer.
    Keywords:  cancer radioresistance; clinically relevant radioresistant (CRR) cells; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3390/genes12091348
  11. Life (Basel). 2021 Aug 27. pii: 885. [Epub ahead of print]11(9):
    Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction.
    Shuhei Suzuki, Masahiro Yamamoto, Tomomi Sanomachi, Keita Togashi, Asuka Sugai, Shizuka Seino, Takashi Yoshioka, Masashi Okada, Chifumi Kitanaka.
      Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.
    Keywords:  ROS; cancer stem cell; dexamethasone
    DOI:  https://doi.org/10.3390/life11090885
  12. Aging (Albany NY). 2021 Sep 27. 13(undefined):
    Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells.
    Kunlun Chen, Pengfei Zhu, Wenhui Chen, Kai Luo, Xiao-Jing Shi, Wenlong Zhai.
      BACKGROUND: Melatonin is an indolic compound mainly secreted by the pineal gland and plays a vital role in the regulation of circadian rhythms and cancer therapy. However, the effects of melatonin in gallbladder cancer (GBC) and the related mechanism remain unknown.METHODS: In this study, the antitumor activity of melatonin on gallbladder cancer was explored both in vitro and in vivo. After treatment with different concentrations of melatonin, the cell viability, migration, and invasion of gallbladder cancer cells (NOZ and GBC-SD cells) were evaluated by CCK-8 assay, wound healing, and Transwell assay.
    RESULTS: The results showed that melatonin inhibited growth, migration, and invasion of gallbladder cancer cells. Subsequently, the assays suggested that melatonin significantly induced apoptosis in gallbladder cancer cells and altered the expression of the apoptotic proteins, including Bax, Bcl-2, cytochrome C, cleaved caspase-3, and PARP. Besides, the intracellular reactive oxygen species (ROS) was found to be upregulated after melatonin treatment in gallbladder cancer cells. Melatonin was found to suppress the PI3K/Akt/mTOR signaling pathway in a time-dependent manner by inhibiting the phosphorylation of PI3K, Akt, and mTOR. Treatment with N-acetyl-L-cysteine (NAC) or 740 Y-P remarkably attenuated the antitumor effects of melatonin in NOZ and GBC-SD cells. Finally, melatonin suppressed the growth of GBC-SD cells in an athymic nude mice xenograft model in vivo.
    CONCLUSIONS: Our study revealed that melatonin could induce apoptosis by suppressing the PI3K/Akt/mTOR signaling pathway. Therefore, melatonin might serve as a potential therapeutic drug in the future treatment of gallbladder cancer.
    Keywords:  PI3K/Akt; ROS; apoptosis; gallbladder cancer; melatonin
    DOI:  https://doi.org/10.18632/aging.203561
  13. Biomaterials. 2021 Sep 18. pii: S0142-9612(21)00492-0. [Epub ahead of print]278 121135
    NIR-triggerable ROS-responsive cluster-bomb-like nanoplatform for enhanced tumor penetration, phototherapy efficiency and antitumor immunity.
    Yu Zhang, Xiyou Du, Shangui Liu, Huixian Yan, Jianbo Ji, Yanwei Xi, Xiaoye Yang, Guangxi Zhai.
      The restricted tumor penetration has been regarded as the Achilles' Heels of most nanomedicines, largely limiting their efficacy. To address this challenge, a cluster-bomb-like nanoplatform named CPIM is prepared, which for the first time combines size-transforming and transcytosis strategies, thus enhancing both passive and active transport. For passive diffusion, the "cluster-bomb" CPIM (135 nm) releases drug-loaded "bomblets" (IR780/1-methyl-tryptophan (1 MT) loaded PAMAM, <10 nm) in response to the high reactive-oxygen-species (ROS) concentration in tumor microenvironment (TME), which promotes intratumoral diffusion. Besides, IR780 generates ROS upon NIR irradiation and intensifies this responsiveness; therefore, there exists a NIR-triggered self-destructive behavior, rendering CPIM spatiotemporal controllability. For active transport, the nanoplatform is proven to be delivered via transcytosis with/without NIR irradiation. Regarding the anti-cancer performance, CPIM strengthens the photodynamic therapy (PDT)/photothermal therapy (PTT) activity of IR780 and IDO pathway inhibition effect of 1 MT, thus exhibiting a strongest inhibitory effect on primary tumor. CPIM also optimally induces immunogenic cell death, reverses the "cold" TME to a "hot" one and evokes systemic immune response, thus exerting an abscopal and anti-metastasis effects. In conclusion, this work provides a facile, simple yet effective strategy to enhance the tumor penetration, tumor-killing effect and antitumor immunity of nanomedicines.
    Keywords:  Immunogenic cell death (ICD); Photodynamic therapy (PDT); Photothermal therapy (PTT); ROS-Responsive; Transcytosis
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121135
  14. Biomolecules. 2021 Aug 31. pii: 1295. [Epub ahead of print]11(9):
    Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells.
    Guoli Li, Sining Fang, Xiao Shao, Yejia Li, Qingchao Tong, Beibei Kong, Lifen Chen, Yanzhong Wang, Jun Yang, Haitao Yu, Xinyou Xie, Jun Zhang.
      Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of 5-FU. The aim of the present study is to explore the effect of Cur on attenuating NNMT-induced resistance to 5-FU in CRC. A panel of CRC cell lines with different NNMT expressions are used to characterize the effect of Cur. Herein, it is observed that Cur can depress the expression of NNMT and p-STAT3 in CRC cells. Furthermore, Cur can induce inhibition of cell proliferation, G2/M phase cell cycle arrest, and reactive oxygen species (ROS) generation, especially in high-NNMT-expression CRC cell lines. Cur can also re-sensitize high-NNMT-expression CRC cells to 5-FU both in vitro and in vivo. In summary, it is proposed that Cur can reverse NNMT-induced cell proliferation and 5-FU resistance through ROS generation and cell cycle arrest. Given that Cur has long been used, we suppose that Cur is a promising anticancer drug candidate with minimal side effects for human CRC therapy and can attenuate NNMT-induced resistance to 5-FU.
    Keywords:  cell cycle arrest; chemoresistance; colorectal cancer; curcumin; nicotinamide N-methyltransferase
    DOI:  https://doi.org/10.3390/biom11091295
  15. Biomedicines. 2021 Sep 13. pii: 1213. [Epub ahead of print]9(9):
    Exploring Hyperoxia Effects in Cancer-From Perioperative Clinical Data to Potential Molecular Mechanisms.
    Anca Irina Ristescu, Crina Elena Tiron, Adrian Tiron, Ioana Grigoras.
      Increased inspiratory oxygen concentration is constantly used during the perioperative period of cancer patients to prevent the potential development of hypoxemia and to provide an adequate oxygen transport to the organs, tissues and cells. Although the primary tumours are surgically removed, the effects of perioperative hyperoxia exposure on distal micro-metastases and on circulating cancer cells can potentially play a role in cancer progression or recurrence. In clinical trials, hyperoxia seems to increase the rate of postoperative complications and, by delaying postoperative recovery, it can alter the return to intended oncological treatment. The effects of supplemental oxygen on the long-term mortality of surgical cancer patients offer, at this point, conflicting results. In experimental studies, hyperoxia effects on cancer biology were explored following multiple pathways. In cancer cell cultures and animal models, hyperoxia increases the production of reactive oxygen species (ROS) and increases the oxidative stress. These can be followed by the induction of the expression of Brain-derived neurotrophic factor (BDNF) and other molecules involved in angiogenesis and by the promotion of various degrees of epithelial mesenchymal transition (EMT).
    Keywords:  BDNF; cancer progression; epithelial mesenchymal transition; hyperoxia; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/biomedicines9091213
  16. Biomedicines. 2021 Aug 28. pii: 1101. [Epub ahead of print]9(9):
    Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress.
    Mei-Chun Chen, Li-Lin Hsu, Sheng-Fan Wang, Yi-Ling Pan, Jeng-Fan Lo, Tien-Shun Yeh, Ling-Ming Tseng, Hsin-Chen Lee.
      Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.
    Keywords:  integrated stress response; oxidative stress; salubrinal; xCT
    DOI:  https://doi.org/10.3390/biomedicines9091101
  17. PLoS One. 2021 ;16(10): e0258115
    Induction of mitochondria mediated apoptosis in human ovarian cancer cells by folic acid coated tin oxide nanoparticles.
    Demiana H Hanna, Gamal R Saad.
      PURPOSE: This study aims to prepare folic acid coated tin oxide nanoparticles (FA-SnO2 NPs) for specifically targeting human ovarian cancer cells with minimum side effects against normal cells.METHODS: The prepared FA-SnO2 NPs were characterized by FT-IR, UV-vis spectroscopy, XRD, SEM and TEM. The inhibition effects of FA-SnO2 NPs against SKOV3 cancer cell were tested by MTT and LDH assay. Apoptosis induction in FA-SnO2 NPs treated SKOV3 cells were investigated using Annexin V/PI, AO/EB and Comet assays and the possible mechanisms of the cytotoxic action were studied by Flow cytometry, qRT-PCR, Immunohistochemistry, and Western blotting analyses. The effects of FA-SnO2 NPs on reactive oxygen species generation in SKOV3 cells were also examined. Additionally, the safety of utilization FA-SnO2 NPs were studied in vivo using Wister rats.
    RESULTS: The obtained FA-SnO2 NPs displayed amorphous spherical morphology with an average diameter of 157 nm and a zeta potential value of -24 mV. Comparing to uncoated SnO2 NPs, FA-SnO2 NPs had a superior inhibition effect towards SKOV3 cell growth that was suggested to be mediated through higher reactive oxygen species generation. It was showed that FA-SnO2 NPs increased significantly the % of apoptotic cells in the sub- G1 and G2/M phases with a higher intensity comet nucleus in SKOV3 treated cells. Furthermore, FA-SnO2 NPs was significantly increased the expression levels of P53, Bax, and cleaved Caspase-3 and accompanied with a significant decrease of Bcl-2 in the treated SKOV3 cells.
    CONCLUSION: Overall, the results suggested that an increase in cellular FA-SnO2 NPs internalization resulted in a significant induced cytotoxicity in SKOV3 cancer cells in dose-dependent mode through ROS-mediated cell apoptosis that may have occurred through mitochondrial pathway. Additionally, the results confirmed the safety of utilization FA-SnO2 NPs against living systems. So, FA-SnO2 NPs with a specific targeting moiety may be a promising therapeutic candidate for human ovarian cancer.
    DOI:  https://doi.org/10.1371/journal.pone.0258115
  18. Cancer Lett. 2021 Sep 24. pii: S0304-3835(21)00492-4. [Epub ahead of print]522 211-224
    SLC7A11/ xCT is a target of miR-5096 and its restoration partially rescues miR-5096-mediated ferroptosis and anti-tumor effects in human breast cancer cells.
    Poonam Yadav, Priyanshu Sharma, Sandhya Sundaram, Ganesh Venkatraman, Amal Kanti Bera, Devarajan Karunagaran.
      Breast cancer cells evade cell death by overexpressing SLC7A11, which functions by transporting cystine into cells in exchange for intracellular glutamate facilitating glutathione synthesis and reducing reactive oxygen species (ROS)-mediated stress. Using an in silico approach, we predicted an miRNA (miR-5096) that can target and downregulate SLC7A11. We demonstrated SLC7A11 as a target of miR-5096 by 3'UTR luciferase assay and further validated it by identifying reduced mRNA and protein levels of SLC7A11 upon miR-5096 overexpression. miR-5096-induced ferroptotic cell death in human breast cancer cells was confirmed by concurrently increased ROS, OH-, lipid ROS, and iron accumulation levels and decreased GSH and mitochondrial membrane potential (MitoTracker™ Orange) with mitochondrial shrinkage and partial cristae loss (observed by TEM). miR-5096 inhibited colony formation, transwell migration, and breast cancer cell invasion, whereas antimiR-5096 promoted these tumorigenic properties. Ectopic expression of SLC7A11 partly reversed miR-5096-mediated effects on cell survival, ROS, lipid peroxides, iron accumulation, GSH, hydroxyl radicals, mitochondrial membrane potential, and colony formation. miR-5096 modulated the expression of epithelial-mesenchymal transition markers in vitro and inhibited the metastatic potential of MDA-MB-231 cells in a tumor xenograft model of zebrafish larvae. Our results demonstrate that miR-5096 is a tumor-suppressive miRNA in breast cancer cells, and this paper discusses its therapeutic implications.
    Keywords:  Ferroptosis; Metastasis; ROS; miRNA; xCT
    DOI:  https://doi.org/10.1016/j.canlet.2021.09.033
  19. Hum Exp Toxicol. 2021 Sep 29. 9603271211047926
    Sesamol induces cytotoxicity via mitochondrial apoptosis in SCC-25 cells.
    D Ezhilarasan, D Ali, R Varghese.
      Sesamol is the main constituent of sesame seed oil and is obtained from Sesamum indicum. Oral squamous cell carcinoma (OSCC) is one of the most common neoplasms affecting the oral cavity. In this study, we investigated the cytotoxic potentials of sesamol on human oral squamous carcinoma (SCC-25) cells. Human oral squamous carcinoma cells were treated with different concentrations (62.5, 125, and 250 μM/mL) of sesamol for 24 h. Cytotoxicity was analyzed by 3- (4, 5- dimethylthiazol -2- yl) -2, 5-diphenyltetrazolium bromide (MTT) assay. Intracellular reactive oxygen species (ROS) expression was investigated by dichloro-dihydro-fluorescein diacetate assay. Apoptosis-related morphology was analyzed by acridine orange/ethidium bromide staining. Caspase-9 expression was analyzed by confocal microscopic double immunofluorescence staining. Mitochondrial apoptosis-related markers are analyzed using qPCR. Sesamol treatment caused a significant cytotoxic effect in OSCC cells. Sesamol-induced cytotoxic effect was associated with intracellular ROS generation. Sesamol treatments induced a significant increase in the early and late apoptotic cells. This treatment also induced caspase-9 expression in OSCC cells. Sesamol treatments caused downregulation of Harvey rat sarcoma viral oncogene homolog (HRAS) expression at protein and gene levels. Sesamol treatment modulates intrinsic apoptotic marker gene expression in OSCC cells. Overall results confirm the anti-cancer potential of sesamol and it seems to be a promising candidate for OSCC.
    Keywords:  Oral cancer; apoptosis; cytotoxicity; reactive oxygen species
    DOI:  https://doi.org/10.1177/09603271211047926
  20. J Colloid Interface Sci. 2021 Sep 11. pii: S0021-9797(21)01508-3. [Epub ahead of print]607(Pt 2): 1516-1526
    A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy.
    Hailong Tian, Sai Zhao, Edouard C Nice, Canhua Huang, Weifeng He, Bingwen Zou, Jie Lin.
      Sorafenib-mediated chemotherapy is currently the first choice for hepatocellular carcinoma (HCC) that cannot be surgically excised, and can significantly improve the survival of patients. However, its poor water solubility restricts its bioavailability, and long-term single use of it does not achieve satisfactory HCC therapy effects. Herein, we report a novel cascaded copper-based metal-organic framework (MOF) therapeutic nanocatalyst using HKUST-1 by integrating cyclooxygenase-2 (COX-2) inhibitor meloxicam (Mel) and chemotherapeutic agent sorafenib (Sol) to amplify HCC therapy. This HKUST-1 nanocatalyst can be degraded by glutathione (GSH) into a Fenton-like agent to trigger chemodynamic therapy (CDT). CDT-mediated cytotoxic reactive oxygen species (ROS) can activate ferroptosis by accumulating lipid peroxides (LPO). Alternatively, GSH depletion not only deactivates glutathione peroxidase 4 (GPX4) to trigger ferroptosis, but also leads to oxidative stress amplification. Moreover, Sol can also activate ferroptosis by inhibiting system XC-, resulting in cascade-amplified ferroptosis mediated HCC therapy. Furthermore, the down-regulation of COX-2 can induce PINK1/Parkin-mediated mitophagy to further act synergistically with Sol-mediated chemotherapy. Therefore, this HKUST-1 nanocatalyst provides a novel strategy to regulate GSH and COX-2 levels for amplified chemo/chemodynamic and ferroptosis-mediated HCC therapy.
    Keywords:  Chemo/chemodynamic therapy; Ferroptosis; Glutathione and cyclooxygenase-2; HKUST-1; Hepatocellular carcinoma
    DOI:  https://doi.org/10.1016/j.jcis.2021.09.049
  21. J Biochem Mol Toxicol. 2021 Sep 29. e22928
    Synergistic effect of anethole and doxorubicin alleviates cell proliferation, cell cycle arrest, and ER stress and promotes ROS-mediated apoptosis in triple-negative breast cancer cells.
    Poornima Arumugam, Banupriya Sampathkumar, Haribalan Perumalsamy, Sri Renukadevi Balusamy, Vignesh Ramesh, Sumathi Sundaravadevel.
      The heterogeneity and poor prognosis of triple-negative breast cancer (TNBC) have limited the treatment options and made clinical management challenging. This has nurtured a major effort to discover druggable molecular targets. Currently, chemotherapy is the primary treatment strategy for this disease. Doxorubicin is the most frequently used chemotherapeutic drug for TNBC and due to the fact that chemotherapeutic drugs have a lot of side effects, we evaluated the synergistic effect of the phytocompound anethole and doxorubicin. The cytotoxic effect of anethole in combination with doxorubicin on MDA-MB-231 cells was evaluated by various parameters, including apoptosis, cell cycle analysis, DNA damage, and cell proliferation. Furthermore, mitochondrial membranepotential (MMP), endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) levels were also evaluated in the cells treated with/without anethole and doxorubicin. Expression of the apoptotic proteins was evaluated by Western blot analysis. Initial evaluation of cytotoxicity of anethole on MDA-MB-231 cells demonstrated preferential suppression of cell proliferation and when treated along with doxorubicin it showed enhanced cytotoxicity with a synergistic effect. Cell cycle analysis revealed arrest at different stages of the cell cycle, such as sub G0-G1, G0-G1, S, and G2M in various treatment groups and apoptotic cell death was subsequently evident with propidium iodide (PI) staining. The synergistic action of anethole and doxorubicin effectively induced mitochondrial membrane potential loss, which, in turn, led to a burst of ROS production, which eventually produced unfolded protein response by damaging the ER. Synergistic anticancer effect was observed on exposure of MDA-MB-231 cells to anethole and doxorubicin in inducing cell death.
    Keywords:  anethole; doxorubicin; reactive oxygen species and apoptosis; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/jbt.22928
  22. Antioxidants (Basel). 2021 Sep 02. pii: 1410. [Epub ahead of print]10(9):
    Nepenthes Ethyl Acetate Extract Provides Oxidative Stress-Dependent Anti-Leukemia Effects.
    Wangta Liu, Li-Ching Lin, Pei-Ju Wang, Yan-Ning Chen, Sheng-Chieh Wang, Ya-Ting Chuang, I-Hsuan Tsai, Szu-Yin Yu, Fang-Rong Chang, Yuan-Bin Cheng, Li-Chen Huang, Ming-Yii Huang, Hsueh-Wei Chang.
      Several kinds of solvents have been applied to Nepenthes extractions exhibiting antioxidant and anticancer effects. However, they were rarely investigated for Nepenthes ethyl acetate extract (EANT), especially leukemia cells. The purpose of the present study was to evaluate the antioxidant properties and explore the antiproliferation impact and mechanism of EANT in leukemia cells. Five standard assays demonstrated that EANT exhibits antioxidant capability. In the cell line model, EANT dose-responsively inhibited cell viabilities of three leukemia cell lines (HL-60, K-562, and MOLT-4) based on 24 h MTS assays, which were reverted by pretreating oxidative stress and apoptosis inhibitors (N-acetylcysteine and Z-VAD-FMK). Due to similar sensitivities among the three cell lines, leukemia HL-60 cells were chosen for exploring antiproliferation mechanisms. EANT caused subG1 and G1 cumulations, triggered annexin V-detected apoptosis, activated apoptotic caspase 3/7 activity, and induced poly ADP-ribose polymerase expression. Moreover, reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization were generated by EANT, which was reverted by N-acetylcysteine. The antioxidant response to oxidative stress showed that EANT upregulated mRNA expressions for nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), thioredoxin (TXN), heme oxygenase 1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. Moreover, these oxidative stresses led to DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) and were alleviated by N-acetylcysteine. Taken together, EANT demonstrated oxidative stress-dependent anti-leukemia ability to HL-60 cells associated with apoptosis and DNA damage.
    Keywords:  DNA damage; Nepenthes; antioxidant; apoptosis; leukemia cells; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10091410
  23. Med Hypotheses. 2021 Sep 20. pii: S0306-9877(21)00202-4. [Epub ahead of print]156 110683
    Receptor based virtual screening of potential novel inhibitors of tigar [TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator.
    Jagadeesha Poyya, D Jagadeesha Kumar, H G Nagendra, B Dinesh, S J Aditya Rao, Chandrashekhar G Joshi.
      TP53 (tumor protein 53)-induced glycolysis and apoptosis regulator (TIGAR) belongs to the phosphatases family of proteins that modulates the level of reactive oxygen species in tumor cells. This protein plays a vital role as a negative regulator of glycolysis, thus lowering ROS levels in the cells, which helps the cancerous cells to resist programmed cell death. Besides, TIGAR also mediates the DNA damage repair in cancer cells by increasing tumor cell survival. In the current study, we have screened natural products that compete with the substrate to bind to the active site of TIGAR. Extra precision and MMGBSA scoring function were used to screen the lead molecules. Five compounds were considered as lead molecules with 2-(2-(3,4-dihydroxy phenyl)-3,5-dihydroxy-8-(4-hydroxyphenyl)-4-oxo-4H-furo[2,3-h]chromen-9-yl) acetic acid(DDFA) as a top lead with a docking score of -9.428, and -53.16 MMGBSA, bind to the positively charged amino acids present in the active site. Further, the molecular dynamics simulation studies indicated the structural stability attained by TIGAR protein upon the binding of DDFA, suggesting it to be a potent inhibitor of TIGAR, and could be employed as an anticancer drug during combinational therapy.
    Keywords:  Apoptosis; Cancer; Phosphatase; Reactive oxygen species; TIGAR
    DOI:  https://doi.org/10.1016/j.mehy.2021.110683
  24. Pharmaceuticals (Basel). 2021 Aug 29. pii: 874. [Epub ahead of print]14(9):
    PRODH/POX-Dependent Celecoxib-Induced Apoptosis in MCF-7 Breast Cancer.
    Magdalena Misiura, Ilona Ościłowska, Katarzyna Bielawska, Jerzy Pałka, Wojciech Miltyk.
      Celecoxib (Cx), an inhibitor of cyclooxygenase 2, induces apoptosis of cancer cells. However, the mechanism of the chemopreventive effect remains not fully understood. We aimed to investigate the role of PRODH/POX that is involved in the regulation of apoptosis induced by celecoxib. MCF-7 breast cancer cell line and the corresponding MCF-7 cell line with silenced PRODH/POX (MCF-7shPRODH/POX) were used. The effects of Cx on cell viability, proliferation, and cell cycle were evaluated. The expressions of protein markers for apoptosis (Bax, caspase 9, and PARP) and autophagy (Atg5, Beclin 1, and LC3A/B) were investigated by Western immunoblotting. To analyze the proline metabolism, collagen biosynthesis, prolidase activity, proline concentration, and the expression of proline-related proteins were evaluated. The generation of ATP, ROS, and the ratio of NAD+/NADH and NADP+/NADPH were determined to test the effect of Cx on energetic metabolism in breast cancer cells. It has been found that Cx attenuated MCF-7 cell proliferation via arresting the cell cycle. Cx induced apoptosis in MCF-7 breast cancer cells, while in MCF-7shPRODH/POX, autophagy occurred more predominantly. In MCF-7 breast cancer cells, Cx affected proline metabolism through upregulation of proline biosynthesis, PRODH/POX and PYCRs expressions, PEPD activity, and downregulation of collagen biosynthesis. In MCF-7shPRODH/POX clones, these processes, as well as energetic metabolism, were remarkably suppressed. The data for the first time suggest that celecoxib induces apoptosis through upregulation of PRODH/POX in MCF-7 breast cancer cells.
    Keywords:  PRODH/POX; apoptosis; breast cancer; proline
    DOI:  https://doi.org/10.3390/ph14090874
  25. Cancers (Basel). 2021 Sep 18. pii: 4677. [Epub ahead of print]13(18):
    Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia.
    Liao Zeng, Mingqing Tang, Chao Pi, Jianrong Zheng, Sanxing Gao, Titaua Chabanne, Remi Chauvin, Wenzhao Cheng, Hongjun Lin, Ruian Xu, Xiuling Cui.
      T cell acute lymphoblastic leukemia (T-ALL) is one of the most common causes of death in pediatric malignancies. However, the clinical chemotherapy for T-ALL has been limited by numerous side effects, emphasizing that novel anti-T-ALL drugs are urgently needed. Herein, a series of 2-acyl-1-dimethylaminomethyl-ferrocenes for cancer therapy have been evaluated. Among them, F1 and F3 exhibited potent cytotoxicity against T-ALL cell lines, especially Jurkat cells, with low cytotoxicity for normal cells. Further mechanistic studies revealed that F1 and F3 could induce apoptosis in Jurkat cells by destructing mitochondrial membrane, enhancing reactive oxygen species (ROS) generation, decreasing the Bcl-2/Bax ratio, releasing Cytochrome c, and increasing the expression of Cleaved Caspase-9/-3 and Cleaved PARP. Additionally, F1 and F3 could suppress cell proliferation and arrest the cell cycle at G0/G1 phase through the PI3K/Akt/mTOR signaling pathway by down-regulating the expression of CDK6, Cyclin D1, p-Akt, p-GSK-3β, p-mTOR, p-p70 S6K, and up-regulating the expression of P21 and P27, which would also be a possible mechanism. Consequently, ferrocene derivatives F1 and F3 could induce apoptosis through a mitochondria-dependent pathway mediated by ROS, and cell cycle arrest at G0/G1 phase via the PI3K/Akt/mTOR signaling pathway in Jurkat cells. The present study provided fundamental insights into the clinical application of F1 and F3 for the treatment of T-ALL.
    Keywords:  PI3K/Akt/mTOR signaling pathway; T cell acute lymphoblastic leukemia; apoptosis; cell cycle; ferrocene derivatives; mitochondrial membrane potential; reactive oxygen species
    DOI:  https://doi.org/10.3390/cancers13184677
  26. Molecules. 2021 Sep 14. pii: 5576. [Epub ahead of print]26(18):
    Oxidative Stress and Multi-Organel Damage Induced by Two Novel Phytocannabinoids, CBDB and CBDP, in Breast Cancer Cells.
    Maria Salbini, Alessandra Quarta, Fabiana Russo, Anna Maria Giudetti, Cinzia Citti, Giuseppe Cannazza, Giuseppe Gigli, Daniele Vergara, Antonio Gaballo.
      Over the last few years, much attention has been paid to phytocannabinoids derived from Cannabis for their therapeutic potential. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant compounds of the Cannabis sativa L. plant. Recently, novel phytocannabinoids, such as cannabidibutol (CBDB) and cannabidiphorol (CBDP), have been discovered. These new molecules exhibit the same terpenophenolic core of CBD and differ only for the length of the alkyl side chain. Roles of CBD homologs in physiological and pathological processes are emerging but the exact molecular mechanisms remain to be fully elucidated. Here, we investigated the biological effects of the newly discovered CBDB or CBDP, compared to the well-known natural and synthetic CBD (nat CBD and syn CBD) in human breast carcinoma cells that express CB receptors. In detail, our data demonstrated that the treatment of cells with the novel phytocannabinoids affects cell viability, increases the production of reactive oxygen species (ROS) and activates cellular pathways related to ROS signaling, as already demonstrated for natural CBD. Moreover, we observed that the biological activity is significantly increased upon combining CBD homologs with drugs that inhibit the activity of enzymes involved in the metabolism of endocannabinoids, such as the monoacylglycerol lipase (MAGL) inhibitor, or with drugs that induces the activation of cellular stress pathways, such as the phorbol ester 12-myristate 13-acetate (PMA).
    Keywords:  MAGL; MCF-7; MJN110; ROS; altered mitochondria; autophagy; cannabidiol; cytoplasmic vacuole; oxidative stress
    DOI:  https://doi.org/10.3390/molecules26185576
  27. Mitochondrion. 2021 Sep 24. pii: S1567-7249(21)00132-X. [Epub ahead of print]
    Simulated microgravity triggers DNA damage and mitochondria-mediated apoptosis through ROS generation in human promyelocytic leukemic cells.
    Ragini Singh, Mohit Rajput, Rana P Singh.
      The weightlessness or microgravity, a physical factor in space, may adversely affect the health of the space travellers or astronauts. The knowledge about the effect of microgravity on human cancer cells is very limited and poorly understood. Here, we employed rotary cell culture system (RCCS) to induce simulated microgravity (SMG) and examined its effects on human promyelocytic leukemic HL-60 cells. These cells were grown in normal gravity condition (1g) for control purpose. The 72 h exposure of cells to SMG decreased cell proliferation and viability which were accompanied by the reduced expression of PCNA and phosphorylated ERK1/2 and AKT proteins. SMG increased the DNA damage as well as the expression of DNA damage sensing proteins including ATM, ATR, Chk1, Chk2 and γH2A.X. The expression of AP1, XRCC1 and APEX1 regulating BER, XPC regulating NER and MLH1 and PMS2 regulating MMR were downregulated. However, SMG increased the expression of Ku70/80, DNA-PK and Rad51, regulating NHEJ and HR. SMG induced apoptosis and increased the levels of cleaved-poly-(ADP-ribose) polymerase and cleaved-caspase-3. An increase in Bax/Bcl-2 ratio and dissipation of mitochondrial membrane potential were also observed. SMG enhanced reactive oxygen species (ROS) formation which led to the enhanced DNA damage and apoptotic cell death. Overall, SMG induced ROS, DNA damage and differential expression of DNA repair genes, and altered the overall DNA repair capacity which may activate ATM/ATR-Chk1/2 and Ku70/80 and DNA-PK-mediated apoptotic cell death.
    Keywords:  Apoptosis; Cancer; DNA damage; DNA repair; Microgravity; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.mito.2021.09.006
  28. Molecules. 2021 Sep 12. pii: 5529. [Epub ahead of print]26(18):
    A Novel Approach to Unraveling the Apoptotic Potential of Rutin (Bioflavonoid) via Targeting Jab1 in Cervical Cancer Cells.
    Pratibha Pandey, Fahad Khan, Faisal Abdulrahman Alzahrani, Huda A Qari, Mohammad Oves.
      Rutin has been well recognized for possessing numerous pharmacological and biological activities in several human cancer cells. This research has addressed the inhibitory potential of rutin against the Jab1 oncogene in SiHa cancer cells, which is known to inactivate various tumor suppressor proteins including p53 and p27. Further, the inhibitory efficacy of rutin via Jab1 expression modulation in cervical cancer has not been yet elucidated. Hence, we hypothesized that rutin could exhibit strong inhibitory efficacy against Jab1 and, thereby, induce significant growth arrest in SiHa cancer cells in a dose-dependent manner. In our study, the cytotoxic efficacy of rutin on the proliferation of a cervical cancer cell line (SiHa) was exhibited using MTT and LDH assays. The correlation between rutin and Jab1 mRNA expression was assessed by RT-PCR analysis and the associated events (a mechanism) with this downregulation were then explored via performing ROS assay, DAPI analysis, and expression analysis of apoptosis-associated signaling molecules such as Bax, Bcl-2, and Caspase-3 and -9 using qRT-PCR analysis. Results exhibit that rutin produces anticancer effects via inducing modulation in the expression of oncogenes as well as tumor suppressor genes. Further apoptosis induction, caspase activation, and ROS generation in rutin-treated SiHa cancer cells explain the cascade of events associated with Jab1 downregulation in SiHa cancer cells. Additionally, apoptosis induction was further confirmed by the FITC-Annexin V/PI double staining method. Altogether, our research supports the feasibility of developing rutin as one of the potent drug candidates in cervical cancer management via targeting one such crucial oncogene associated with cervical cancer progression.
    Keywords:  Caspase-3; Jab1; ROS; apoptosis; cervical cancer; oncogene; rutin
    DOI:  https://doi.org/10.3390/molecules26185529
  29. Cells. 2021 Sep 20. pii: 2486. [Epub ahead of print]10(9):
    Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled.
    Ronit Vogt Sionov.
      Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil-tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.
    Keywords:  Cathepsin G; NETs; RAGE; TRAIL; cancer; chemokines; chronic inflammation; metastasis; neutrophils; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells10092486
  30. Antioxidants (Basel). 2021 Sep 05. pii: 1419. [Epub ahead of print]10(9):
    Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma.
    Nidhi Sharma, Subhrajit Biswas, Noura Al-Dayan, Alaa Saud Alhegaili, Maryam Sarwat.
      Reactive oxygen species (ROS) are noxious to cells because their increased level interacts with the body's defense mechanism. These species also cause mutations and uncontrolled cell division, resulting in oxidative stress (OS). Prolonged oxidative stress is responsible for incorrect protein folding in the endoplasmic reticulum (ER), causing a stressful condition, ER stress. These cellular stresses (oxidative stress and ER stress) are well-recognized biological factors that play a prominent role in the progression of hepatocellular carcinoma (HCC). HCC is a critical global health problem and the third leading cause of cancer-related mortality. The application of anti-oxidants from herbal sources significantly reduces oxidative stress. Kaempferol (KP) is a naturally occurring, aglycone dietary flavonoid that is present in various plants (Crocus sativus, Coccinia grandis, Euphorbia pekinensis, varieties of Aloe vera, etc.) It is capable of interacting with pleiotropic proteins of the human body. Efforts are in progress to develop KP as a potential candidate to prevent HCC with no adverse effects. This review emphasizes the molecular mechanism of KP for treating HCC, targeting oxidative stress.
    Keywords:  ER stress; HCC; anti-oxidants; free radicals; kaempferol; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10091419
  31. Front Pharmacol. 2021 ;12 734774
    The Novel Antioxidant Compound JSH-23 Prevents Osteolysis by Scavenging ROS During Both Osteoclastogenesis and Osteoblastogenesis.
    Liangwei Mei, Yi Zheng, Teng Ma, Bing Xia, Xue Gao, Yiming Hao, Zhuojing Luo, Jinghui Huang.
      Inflammatory osteolysis is a pathological skeletal disease associated with not only the production of inflammatory cytokines but also local oxidative status. Excessive reactive oxygen species (ROS) promote bone resorption by osteoclasts and induce the apoptosis of osteoblasts. In consideration of the lack of effective preventive or treatments options against osteolysis, the exploitation of novel pharmacological compounds/agents is critically required. In our study, we found that a novel antioxidant compound, JSH-23, plays a role in restoring bone homeostasis by scavenging intracellular ROS during both osteoclastogenesis and osteoblastogenesis. Mechanically, JSH-23 suppressed RANKL-induced osteoclastogenesis, bone resorption and the expression of specific genes (including NFATc1, c-Fos, TRAP, CTSK and DC-STAMP) via inhibition of the NF-κB signaling pathway. Meanwhile, JSH-23 suppressed RANKL-induced ROS generation via the TRAF6/Rac1/NOX1 pathway and the enhanced expression of Nrf2/HO-1. In addition, JSH-23 attenuated H2O2-induced apoptosis and mineralization reduction in osteoblasts by reducing ROS production and enhancing Nrf2/HO-1 expression. Our in vivo results further revealed that JSH-23 exerts its protective effects on bone mass through its antioxidant activity. In conclusion, our results show that the application of JSH-23 might be a novel and plausible strategy for the treatment of osteolysis-related disease.
    Keywords:  HO-1 (heme oxygenase-1); JSH-23 (PubChem CID: 16760588); Nrf2; ROS–reactive oxygen species; osteoblast (OB); osteoclast (OC)
    DOI:  https://doi.org/10.3389/fphar.2021.734774
  32. Pharmaceutics. 2021 Aug 27. pii: 1345. [Epub ahead of print]13(9):
    Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy.
    Sherif Ashraf Fahmy, Hassan Mohamed El-Said Azzazy, Jens Schaefer.
      Photodynamic therapy (PDT) is a promising non-invasive strategy in the fight against that which circumvents the systemic toxic effects of chemotherapeutics. It relies on photosensitizers (PSs), which are photoactivated by light irradiation and interaction with molecular oxygen. This generates highly reactive oxygen species (such as 1O2, H2O2, O2, ·OH), which kill cancer cells by necrosis or apoptosis. Despite the promising effects of PDT in cancer treatment, it still suffers from several shortcomings, such as poor biodistribution of hydrophobic PSs, low cellular uptake, and low efficacy in treating bulky or deep tumors. Hence, various nanoplatforms have been developed to increase PDT treatment effectiveness and minimize off-target adverse effects. Liposomes showed great potential in accommodating different PSs, chemotherapeutic drugs, and other therapeutically active molecules. Here, we review the state-of-the-art in encapsulating PSs alone or combined with other chemotherapeutic drugs into liposomes for effective tumor PDT.
    Keywords:  cancer; liposomes; photodynamic therapy; photosensitizers; stealth liposomes; tetraether lipids; thermosensitive liposomes
    DOI:  https://doi.org/10.3390/pharmaceutics13091345
  33. Int J Mol Sci. 2021 Sep 10. pii: 9796. [Epub ahead of print]22(18):
    Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis.
    Elmira Khusnutdinova, Anastasiya Petrova, Zulfia Zileeva, Ulyana Kuzmina, Liana Zainullina, Yulia Vakhitova, Denis Babkov, Oxana Kazakova.
      A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose-response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs. Among the oleanane type triterpenoids, C2-[4-pyridinylidene]-oleanonic C28-morpholinyl amide exhibited sub-micromolar potencies against 15 different tumor cell lines and revealed particular selectivity for non-small cell lung cancer (HOP-92) with a GI50 value of 0.0347 μM. On the other hand, superior results were observed for C2-[3-pyridinylidene]-ursonic N-methyl-piperazinyl amide 29, which exhibited a broad-spectrum inhibition activity with GI50 < 1 μM against 33 tumor cell lines and <2 μM against all 60 cell lines. This compound has been further evaluated for cell cycle analysis to decipher the mechanism of action. The data indicate that compound 29 could exhibit both cytostatic and cytotoxic activity, depending on the cell line evaluated. The cytostatic activity appears to be determined by induction of the cell cycle arrest at the S (MCF-7, SH-SY5Y cells) or G0/G1 phases (A549 cells), whereas cytotoxicity of the compound against normal cells is nonspecific and arises from apoptosis without significant alterations in cell cycle distribution (HEK293 cells). Our results suggest that the antiproliferative effect of compound 29 is mediated through ROS-triggered apoptosis that involves mitochondrial membrane potential depolarization and caspase activation.
    Keywords:  CellMiner; Claisen-Schmidt reaction; NCI-60; anticancer activity; apoptosis; network-like similarity graphs; oleanolic acid; ursolic acid
    DOI:  https://doi.org/10.3390/ijms22189796
  34. Adv Healthc Mater. 2021 Sep 29. e2101174
    Soft X-Ray Stimulated Lanthanide@MOF Nanoprobe for Amplifying Deep Tissue Synergistic Photodynamic and Antitumor Immunotherapy.
    Xiaoting Zhao, Youbin Li, Linman Du, Zhiming Deng, Mingyang Jiang, Songjun Zeng.
      Combining photodynamic therapy (PDT) and immunotherapy has shown profound impact for synergistic treatment of malignant tumors. However, the shallow penetration depth of the traditional visible light activated PDT, immunosuppressive tumor microenvironment (TME), and poor immunogenicity of deep-seated solid tumors have significantly impeded the therapeutic efficiency. Herein, a soft X-ray activated nanoprobe is rationally engineered via integrating porphyrin Zr-based metal-organic framework with lanthanide NaYF4 :Gd,Tb@NaYF4 scintillator nanoparticles (SNPs) by a new in situ growth strategy for synergistic PDT and immunotherapy of tumor. The nanoprobe possesses remarkably enhanced reactive oxygen species (ROS) generation triggered by soft X-ray via further covalently grafting rose bengal on the nanoprobe, even at tissue depths of 3 cm. Moreover, the soft X-ray induced ROS can act as potential immunogenic cell death (ICD) trigger, subsequently leading to the activation of the adaptive antitumor immune-response. Significantly, the boosted ROS generation can further modulate the immunosuppressive TME. This work provides new strategy of designing antitumor nanoprobes for soft X-ray triggered deep-tissue PDT and immune response, breaking the depth barriers suffered by the traditional photoactivated PDT or ICD using visible and near infrared light.
    Keywords:  antitumor photodynamic-immunotherapy; explosive ROS generation; lanthanide metal-organic frameworks; photoactivated nanovaccines; soft X-ray
    DOI:  https://doi.org/10.1002/adhm.202101174
  35. Int J Mol Sci. 2021 Sep 19. pii: 10126. [Epub ahead of print]22(18):
    Dark Side of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, and Immune Modulation.
    Ettickan Boopathi, Chellappagounder Thangavel.
      Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is one of the most undesirable side effects of cancer therapy and leads to limitations to cancer treatment. Chemoradiation therapy or immunotherapy promote acute and chronic cardiopulmonary damage by inducing reactive oxygen species, DNA damage, inflammation, fibrosis, deregulation of cellular immunity, cardiopulmonary failure, and non-malignant related deaths among cancer-free patients who received cancer therapy. CTRCPD is a complex entity with multiple factors involved in this pathogenesis. Although the mechanisms of cancer therapy-induced toxicities are multifactorial, damage to the cardiac and pulmonary tissue as well as subsequent fibrosis and organ failure seem to be the underlying events. The available biomarkers and treatment options are not sufficient and efficient to detect cancer therapy-induced early asymptomatic cell fate cardiopulmonary toxicity. Therefore, application of cutting-edge multi-omics technology, such us whole-exome sequencing, DNA methylation, whole-genome sequencing, metabolomics, protein mass spectrometry and single cell transcriptomics, and 10 X spatial genomics, are warranted to identify early and late toxicity, inflammation-induced carcinogenesis response biomarkers, and cancer relapse response biomarkers. In this review, we summarize the current state of knowledge on cancer therapy-induced cardiopulmonary complications and our current understanding of the pathological and molecular consequences of cancer therapy-induced cardiopulmonary fibrosis, inflammation, immune suppression, and tumor recurrence, and possible treatment options for cancer therapy-induced cardiopulmonary toxicity.
    Keywords:  antioxidants; cardiopulmonary inflammation; chemoradiation; fibroblast; fibrosis; immunity; immunotherapy; inflammation; programmed death ligand-1; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms221810126
  36. Front Mol Biosci. 2021 ;8 720370
    Hydroxychloroquine Induces Apoptosis in Cholangiocarcinoma via Reactive Oxygen Species Accumulation Induced by Autophagy Inhibition.
    Jiaqi Chen, Qiaoya Pan, Yang Bai, Xuepeng Chen, Yi Zhou.
      Purpose: Despite considerable efforts to improve treatment modalities for cholangiocarcinoma, a common form of malignant tumor, its long-term survival rate remains poor. Hydroxychloroquine (HCQ) is a 4-aminoquinoline derivative antimalarial drug that has antimalarial and autophagy inhibition effects and exhibits comprehensive therapeutic effects on various cancers. In this study, we aimed to explore the anticancer potential and the underlying molecular mechanism of HCQ in cholangiocarcinoma treatment in vitro and in vivo. Methods: Autophagy-related genes (ARGs) were obtained from the Human Autophagy Database and Molecular Signatures Database, and the expression profiles of ARGs were downloaded from the database of The Cancer Genome Atlas. Different expression gene sets were performed using R software. The Gene Ontology and KEGG enrichment analyses were performed to reveal significantly enriched signaling pathways and to identify differentially expressed genes in cholangiocarcinoma tissues. HuCCT-1 and CCLP-1 cells were exposed to different concentrations of HCQ. Cell proliferation was detected by Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell apoptosis and cycle arrest were detected by the Live/Dead cell assay and flow cytometry (FCM). The inhibition of autophagy was observed using fluorescence microscopy. The reactive oxygen species levels were assessed by fluorescence microscopy and flow cytometry. The protein levels were determined by western blot. A cholangiocarcinoma cell line xenograft model was used to evaluate the antitumor activity of HCQ in vivo. Results: Compared with normal tissues, there were 141 ARGs with an aberrant expression in cholangiocarcinoma tissues which were mainly enriched in autophagy-related processes. Inhibition of autophagy by HCQ effectively suppressed cholangiocarcinoma in vitro and in vivo. HCQ inhibited cell proliferation and induced apoptosis and cycle arrest in vitro by increasing ROS accumulation, which was involved in autophagy inhibition. The ROS scavenger reduced l-glutathione distinctly weakened HCQ-induced cell apoptosis and viability inhibition in cholangiocarcinoma cells. In addition, HCQ inhibited growth of cholangiocarcinoma cell line xenograft tumors. Conclusion: HCQ could inhibit cell proliferation and induce apoptosis in cholangiocarcinoma by triggering ROS accumulation via autophagy inhibition, which makes HCQ a potential antitumor drug candidate for cholangiocarcinoma treatment.
    Keywords:  HCQ; ROS; TCGA; autophagy; cholangiocarcinoma
    DOI:  https://doi.org/10.3389/fmolb.2021.720370
  37. Cells. 2021 Aug 25. pii: 2190. [Epub ahead of print]10(9):
    Redox-Sensitive and Folate-Receptor-Mediated Targeting of Cervical Cancer Cells for Photodynamic Therapy Using Nanophotosensitizers Composed of Chlorin e6-Conjugated β-Cyclodextrin via Diselenide Linkage.
    Howard Kim, Mi Woon Kim, Young-Il Jeong, Hoe Saeng Yang.
      The aim of this study was to fabricate a reactive oxygen species (ROS)-sensitive and folate-receptor-targeted nanophotosensitizer for the efficient photodynamic therapy (PDT) of cervical carcinoma cells. Chlorin e6 (Ce6) as a model photosensitizer was conjugated with succinyl β-cyclodextrin via selenocystamine linkages. Folic acid (FA)-poly(ethylene glycol) (PEG) (FA-PEG) conjugates were attached to these conjugates and then FA-PEG-succinyl β-cyclodextrin-selenocystamine-Ce6 (FAPEGbCDseseCe6) conjugates were synthesized. Nanophotosensitizers of FaPEGbCDseseCe6 conjugates were fabricated using dialysis membrane. Nanophotosensitizers showed spherical shapes with small particle sizes. They were disintegrated in the presence of hydrogen peroxide (H2O2) and particle size distribution changed from monomodal distribution pattern to multimodal pattern. The fluorescence intensity and Ce6 release rate also increased due to the increase in H2O2 concentration, indicating that the nanophotosensitizers displayed ROS sensitivity. The Ce6 uptake ratio, ROS generation and cell cytotoxicity of the nanophotosensitizers were significantly higher than those of the Ce6 itself against HeLa cells in vitro. Furthermore, the nanophotosensitizers showed folate-receptor-specific delivery capacity and phototoxicity. The intracellular delivery of nanophotosensitizers was inhibited by folate receptor blocking, indicating that they have folate-receptor specificity in vitro and in vivo. Nanophotosensitizers showed higher efficiency in inhibition of tumor growth of HeLa cells in vivo compared to Ce6 alone. These results show that nanophotosensitizers of FaPEGbCDseseCe6 conjugates are promising candidates as PDT of cervical cancer.
    Keywords:  ROS-sensitive; cervical cancer; folate receptor; nanophotosensitizer; photodynamic therapy
    DOI:  https://doi.org/10.3390/cells10092190
  38. Free Radic Biol Med. 2021 Sep 28. pii: S0891-5849(21)00744-9. [Epub ahead of print]
    The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer.
    Fabrizio Fontana, Patrizia Limonta.
      Mitochondria are the cytoplasmic organelles mostly known as the "electric engine" of the cells; however, they also play pivotal roles in different biological processes, such as cell growth/apoptosis, Ca2+ and redox homeostasis, and cell stemness. In cancer cells, mitochondria undergo peculiar functional and structural dynamics involved in the survival/death fate of the cell. Cancer cells use glycolysis to support macromolecular biosynthesis and energy production ("Warburg effect"); however, mitochondrial OXPHOS has been shown to be still active during carcinogenesis and even exacerbated in drug-resistant and stem cancer cells. This metabolic rewiring is associated with mutations in genes encoding mitochondrial metabolic enzymes ("oncometabolites"), alterations of ROS production and redox biology, and a fine-tuned balance between anti-/proapoptotic proteins. In cancer cells, mitochondria also experience dynamic alterations from the structural point of view undergoing coordinated cycles of biogenesis, fusion/fission and mitophagy, and physically communicating with the endoplasmic reticulum (ER), through the Ca2+ flux, at the MAM (mitochondria-associated membranes) levels. This review addresses the peculiar mitochondrial metabolic and structural dynamics occurring in cancer cells and their role in coordinating the balance between cell survival and death. The role of mitochondrial dynamics as effective biomarkers of tumor progression and promising targets for anticancer strategies is also discussed.
    Keywords:  Cancer; MAMs; Metabolic rewiring; Mitochondria; OXPHOS; ROS; Structural dynamics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.024
  39. Cancers (Basel). 2021 Sep 10. pii: 4549. [Epub ahead of print]13(18):
    Therapeutic ROS and Immunity in Cancer-The TRIC-21 Meeting.
    Sander Bekeschus, Steffen Emmert, Ramona Clemen, Lars Boeckmann.
      The first Therapeutic ROS and Immunity in Cancer (TRIC) meeting was organized by the excellence research center ZIK plasmatis (with its previous Frontiers in Redox Biochemistry and Medicine (FiRBaM) and Young Professionals' Workshop in Plasma Medicine (YPWPM) workshop series in Northern Germany) and the excellence research program ONKOTHER-H (Rostock/Greifswald, Germany). The meeting showcased cutting-edge research and liberated discussions on the application of therapeutic ROS and immunology in cancer treatment, primarily focusing on gas plasma technology. The 2-day hybrid meeting took place in Greifswald and online from 15-16 July 2021, facilitating a wide range of participants totaling 66 scientists from 12 countries and 5 continents. The meeting aimed at bringing together researchers from a variety of disciplines, including chemists, biochemists, biologists, engineers, immunologists, physicists, and physicians for interdisciplinary discussions on using therapeutic ROS and medical gas plasma technology in cancer therapy with the four main sessions: "Plasma, Cancer, Immunity", "Plasma combination therapies", "Plasma risk assessment and patients studies", and "Plasma mechanisms and treated liquids in cancer". This conference report outlines the abstracts of attending scientists submitted to this meeting.
    Keywords:  RNS; cold physical plasma; combination therapy; medical gas plasma technology; oncology; reactive oxygen species; tumor immunology
    DOI:  https://doi.org/10.3390/cancers13184549
  40. Cancer Res. 2021 Sep 30. pii: canres.0061.2021. [Epub ahead of print]
    MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia.
    Kumar Sanjiv, José Manuel Calderón-Montaño, Therese M Pham, Tom Erkers, Viktoriia Tsuber, Ingrid Almlöf, Andreas Höglund, Yaser Heshmati, Brinton Seashore-Ludlow, Akhilesh Nagesh Danda, Helge Gad, Elisee Wiita, Camilla Göktürk, Azita Rasti, Stefanie Friedrich, Anders Centio, Montserrat Estruch, Thea Kristin Våtsveen, Nona Struyf, Torkild Visnes, Martin Scobie, Tobias Koolmeister, Martin Henriksson, Olov Wallner, Teresa Sandvall, Sören Lehmann, Kim Theilgaard-Mönch, Mathew J Garnett, Päivi Östling, Julian Walfridsson, Thomas Helleday, Ulrika Warpman Berglund.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematological cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin-CD34+CD38-),which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0061
  41. Front Oncol. 2021 ;11 682710
    SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism.
    Yong Wang, Jiawen Gao, Shasha Hu, Weiting Zeng, Hongjun Yang, Hui Chen, Shuang Wang.
      Background: Bladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown.Methods: The expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa.
    Results: We found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway.
    Conclusions: Our findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.
    Keywords:  ROS; SLC25A21; apoptosis; bladder cancer; α-ketoglutarate
    DOI:  https://doi.org/10.3389/fonc.2021.682710
  42. Antioxidants (Basel). 2021 Sep 14. pii: 1456. [Epub ahead of print]10(9):
    Betulinic Acid-Doxorubicin-Drug Combination Induced Apoptotic Death via ROS Stimulation in a Relapsed AML MOLM-13 Cell Model.
    Milan Vu, Nick Kassouf, Sandra Appiah.
      In this study, cell death regulation and induction in AML cell line from a relapsed MLL-rearranged cell model (MOLM-13) was investigated with doxorubin (Dox) and betulinic acid (BetA), singly and in combination. CyQUANT Direct® and Annexin V/propidium iodide double staining were used to measure the cytotoxic and cell death induction effects of the compounds, respectively. Reactive oxygen species (ROS) generation was measured using 2',7'-dichlorofluorescin diacetate staining. Expressions of proteins and genes were examined by Western blot and reverse transcription polymerase chain reaction analysis, respectively. BetA (20 μM) and Dox (1 μM) indicated a synergistic growth inhibitory effect on MOLM-13 cells. The combined drug caused more cells to reside in irreversible late apoptotic stage compared to the single treatments (p < 0.05). Elevation in ROS may be the synergistic mechanism involved in MOLM-13 cell death since ROS can directly disrupt mitochondrial activity. In contrast, in leukaemic U-937 cells, the combination treatments attenuated Dox-induced cell death. Dox and the drug combination selectively reduced (p < 0.05) a recently reported anti-apoptotic Bcl-2 protein isoform p15-20-Bcl-2 in MOLM-13 by our group, without affecting the usually reported p26-Bcl-2-α. Further studies using known inhibitors of apoptosis are required to confirm the potential of Dox-BetA combination to modulate these pathways.
    Keywords:  B-cell lymphoma 2 family of proteins; acute myeloid leukaemia; apoptosis; betulinic acid; doxorubicin; drug combination; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox10091456
  43. Cells. 2021 Sep 13. pii: 2401. [Epub ahead of print]10(9):
    The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival.
    Shih-Kai Chiang, Shuen-Ei Chen, Ling-Chu Chang.
      Heme oxygenases (HOs) act on heme degradation to produce carbon monoxide (CO), free iron, ferritin, and biliverdin. Upregulation of cellular HO-1 levels is signature of oxidative stress for its downstream effects particularly under pro-oxidative status. Subcellular traffics of HO-1 to different organelles constitute a network of interactions compromising a variety of effectors such as pro-oxidants, ROS, mitochondrial enzymes, and nucleic transcription factors. Some of the compartmentalized HO-1 have been demonstrated as functioning in the progression of cancer. Emerging data show the multiple roles of HO-1 in tumorigenesis from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy. However, the role of HO-1 in tumorigenesis has not been systematically addressed. This review describes the crosstalk between HO-1 and oxidative stress, and following redox regulation in the tumorigenesis. HO-1-regulated signaling pathways are also summarized. This review aims to integrate basic information and current progress of HO-1 in cancer research in order to enhance the understandings and facilitate following studies.
    Keywords:  cancers; heme oxygenase-1; mitochondria; nuclei; reactive oxygen species; subcellular localization
    DOI:  https://doi.org/10.3390/cells10092401
  44. Proteomics. 2021 Sep 26. e2100094
    Proteomics analysis reveals the correlation of programmed ROS-autophagy loop and dysregulated G1/S checkpoint with imatinib resistance in Chronic Myeloid Leukemia cells.
    Xiucai Xu, Shihong Yin, Yingli Ren, Chaojie Hu, Aimei Zhang, Ya Lin.
      Although tyrosine kinase inhibitors (TKIs), including imatinib, have greatly improved clinical treatment of patients with chronic myeloid leukemia (CML), drug resistance remains a major obstacle. Studies on the mechanisms underlying imatinib resistance and other alternative drugs are urgently needed. Liquid chromatography tandem mass spectrometry was applied to investigate the differences in proteomics and phosphoproteomics between K562 and K562/G (imatinib resistant K562). Multiple bioinformatics analyses were performed to unveil the differential signal pathways. CCK-8 was used to detect cell proliferation. Flow cytometry was performed to analyze ROS, cell cycle and cell apoptosis. Western blotting and qRT-PCR were used to observe the changes of ROS and autophagy associated with imatinib resistance in CML. Our results indicated that ROS-autophagy formed one negative feedback loop and was associated with imatinib resistance. Additionally, the limited-rate enzymes of serine synthesis pathway were escalated in K562/G, which could contributed to the increased cyclin-dependent kinases and cell proliferation index. According to phosphoproteomics data, K562/G cells exhibited abnormal phosphorylation of splicing signals. These results revealed that it could be one useful strategy to correct metabolism shift and oxidative stress, or moderately regulate autophagy. Future research should focus on the discovery of potential targets in ROS-autophagy loop. This article is protected by copyright. All rights reserved.
    Keywords:  Autophagy; Chronic myeloid leukemia; Imatinib; Proteomics; Reactive oxygen species
    DOI:  https://doi.org/10.1002/pmic.202100094
  45. Clin Transl Med. 2021 Sep;11(9): e517
    Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.
    Wenwen Liu, Yang Zhou, Wenzhe Duan, Jing Song, Song Wei, Shengkai Xia, Yingyan Wang, Xiaohui Du, Encheng Li, Caixia Ren, Wei Wang, Qimin Zhan, Qi Wang.
      BACKGROUND: Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown.METHODS: Platinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain-of-function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay.
    RESULTS: The derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM.
    CONCLUSIONS: Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.
    Keywords:  GPX4 inhibitor; brain metastasis; chemotherapeutic resistance; ferroptosis; glutathione metabolism; lung cancer
    DOI:  https://doi.org/10.1002/ctm2.517
  46. Anal Chem. 2021 Sep 28.
    Molecular Design of Monochromophore-Based Bifunctional Photosensitizers for Simultaneous Ratiometric Oxygen Reporting and Photodynamic Cancer Therapy.
    Zhen Zhang, Chao Shi, Xiang Xia, Jianjun Du, Jiangli Fan, Xiaojun Peng.
      Monitoring the tumor oxygen level when implementing photodynamic therapy (PDT) on malignant cancer has vital significance but remains challenging yet. Herein, by structurally manipulating a 2,4-dimethylpyrrole-engineered asymmetric BODIPY scaffold with different kinds, numbers, and positions of halogen atoms, we rationally designed several monochromophore-based bifunctional photosensitizers, named BDPs (BDP-I, BDP-II, and BDP-III), with self-sensitized photooxidation characteristics for accurate oxygen reporting and photodynamic tumor ablation. We show that different ways of halogen regulation allow available tuning of BDPs' oxygen-dependent ratiometric fluorescence turn-ons upon light irradiation as well as type-II PDT efficiencies before and after self-sensitized photooxidation. Encouragingly, measuring the specific ratiometric signals of the most promising BDP-II enabled the direct observation of initial oxygen concentration in both living 4T1 cells and a tumor-bearing mice model, affording an alternative way for evaluating oxygen supplementation strategies. Meanwhile, the "always on" PDT effect of BDP-II ensured efficient tumor ablation via apoptosis. Our research was thus believed to be of instructive significance for future application of oxygen-related auxiliary strategies and the design of unimolecular multifunctional PDT agents for cancer precision therapy.
    DOI:  https://doi.org/10.1021/acs.analchem.1c02485
  47. Antioxidants (Basel). 2021 Sep 14. pii: 1459. [Epub ahead of print]10(9):
    7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway.
    Lifang Wang, Hack Sun Choi, Yan Su, Binna Lee, Jae Jun Song, Yong-Suk Jang, Jeong-Woo Seo.
      Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment (TME). Tumor-associated macrophages (TAM) are known to mediate colorectal cancer metastasis and relapse and are therefore a promising therapeutic target. In the current study, we first confirmed the anti-inflammatory effect of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), a novel DHA dihydroxy derivative synthesized in our previous work. We found that diHEP-DPA significantly reduced lipopolysaccharide (LPS)-induced inflammatory cytokines secretion of THP1 macrophages, IL-6, and TNF-α. As expected, diHEP-DPA also modulated TAM polarization, as evidenced by decreased gene and protein expression of the TAM markers, CD206, CD163, VEGF, and TGF-β1. During the polarization process, diHEP-DPA treatment decreased the concentration of TGF-β1, IL-1β, IL-6, and TNF-α in culture supernatants via inhibiting the NF-κB pathway. Moreover, diHEP-DPA blocked immunosuppression by reducing the expression of SIRPα in TAMs and CD47 in colorectal cancer cells. Knowing that an inflammatory TME largely serves to support epithelial-mesenchymal transition (EMT) and cancer stemness, we tested whether diHEP-DPA acted through polarization of TAMs to regulate these processes. The intraperitoneally injected diHEP-DPA inhibited tumor growth when administered alone or in combination with 5-fluorouracil (5-FU) chemotherapy in vivo. We further found that diHEP-DPA effectively reversed TAM-conditioned medium (TCCM)-induced EMT and enhanced colorectal cancer stemness, as evidenced by its inhibition of colorectal cancer cell migration, invasion and expression of EMT markers, as well as cancer cell tumorspheres formation, without damaging colorectal cancer cells. DiHEP-DPA reduced the population of aldehyde dehydrogenase (ALDH)-positive cells and expression of colorectal stemness marker proteins (CD133, CD44, and Sox2) by modulating TAM polarization. Additionally, diHEP-DPA directly inhibited cancer stemness by inducing the production of reactive oxygen species (ROS), which, in turn, reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). These data collectively suggest that diHEP-DPA has the potential for development as an anticancer agent against colorectal cancer.
    Keywords:  7,15,16,17-epoxy-tetrahydroxy docosahexaenoic acid (diHEP-DPA); ROS; STAT3; colorectal cancer stemness; epithelial-mesenchymal transition (EMT); tumor-associated macrophages
    DOI:  https://doi.org/10.3390/antiox10091459
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