bims-rehoca Biomed News
on Redox homeostasis in cancer
Issue of 2021‒10‒24
thirty-nine papers selected by
Vittoria Raimondi
Veneto Institute of Oncology
  1. Soft Coral-Derived Dihydrosinularin Exhibits Antiproliferative Effects Associated with Apoptosis and DNA Damage in Oral Cancer Cells.
  2. Stimulation of ROS Generation by Extract of Warburgia ugandensis Leading to G0/G1 Cell Cycle Arrest and Antiproliferation in A549 Cells.
  3. Reactive Oxygen Species Mediate 6c-Induced Mitochondrial and Lysosomal Dysfunction, Autophagic Cell Death, and DNA Damage in Hepatocellular Carcinoma.
  4. Xanthorrhizol inhibits non-small cell carcinoma (A549) cell growth and promotes apoptosis through modulation of PI3K/AKT and NF-κB signaling pathway.
  5. Pulsed electromagnetic field potentiates etoposide-induced MCF-7 cell death.
  6. Burmannic Acid Inhibits Proliferation and Induces Oxidative Stress Response of Oral Cancer Cells.
  7. Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities.
  8. Redox Control of the Dormant Cancer Cell Life Cycle.
  9. Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells.
  10. Combinative treatment of Curdione and docetaxel triggers reactive oxygen species (ROS)-mediated intrinsic apoptosis of triple-negative breast cancer cells.
  11. The Cytotoxicity of Doxorubicin Can Be Accelerated by a Combination of Hyperthermia and 5-Aminolevulinic Acid.
  12. Screening compound libraries for H2O2-mediated cancer therapeutics using a peroxiredoxin-based sensor.
  13. Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells.
  14. Induction of Apoptosis by Isoalantolactone in Human Hepatocellular Carcinoma Hep3B Cells through Activation of the ROS-Dependent JNK Signaling Pathway.
  15. Roles of Fibroblasts in Microenvironment Formation Associated with Radiation-Induced Cancer.
  16. Hypoxically cultured cells of oral squamous cell carcinoma increased their glucose metabolic activity under normoxic conditions.
  17. Myoglobin Protects Breast Cancer Cells Due to Its ROS and NO Scavenging Properties.
  18. FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells.
  19. Nanosonosensitizers With Ultrasound-Induced Reactive Oxygen Species Generation for Cancer Sonodynamic Immunotherapy.
  20. Berberine Photo-Activation Potentiates Cytotoxicity in Human Astrocytoma Cells through Apoptosis Induction.
  21. Phytochemicals from Indian Ethnomedicines: Promising Prospects for the Management of Oxidative Stress and Cancer.
  22. Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: Reducing Radicals to Refine Responses.
  23. Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis.
  24. Role of NRF2 cascade in determining the differential response of cervical cancer cells to anticancer drugs: an in vitro study.
  25. Sodium Butyrate Enhances Curcuminoids Permeability through the Blood-Brain Barrier, Restores Wnt/β-Catenin Pathway Antagonists Gene Expression and Reduces the Viability of Glioblastoma Cells.
  26. Latest Innovations and Nanotechnologies with Curcumin as a Nature-Inspired Photosensitizer Applied in the Photodynamic Therapy of Cancer.
  27. Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells.
  28. Preclinical and Clinical Antioxidant Effects of Natural Compounds against Oxidative Stress-Induced Epigenetic Instability in Tumor Cells.
  29. Trojan Horse-Like Nano-AIE Aggregates Based on Homologous Targeting Strategy and Their Photodynamic Therapy in Anticancer Application.
  30. Crucial Role of Reactive Oxygen Species (ROS) for the Proapoptotic Effects of Indirubin Derivatives in Cutaneous SCC Cells.
  31. Electron Donors Rather Than Reactive Oxygen Species Needed for Therapeutic Photochemical Reaction of Near-Infrared Photoimmunotherapy.
  32. Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor.
  33. Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.
  34. Acacetin Inhibits the Growth of STAT3-Activated DU145 Prostate Cancer Cells by Directly Binding to Signal Transducer and Activator of Transcription 3 (STAT3).
  35. Baicalin Enhances Chemosensitivity to Doxorubicin in Breast Cancer Cells via Upregulation of Oxidative Stress-Mediated Mitochondria-Dependent Apoptosis.
  36. Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst.
  37. Corosolic acid reduces A549 and PC9 cell proliferation, invasion, and chemoresistance in NSCLC via inducing mitochondrial and liposomal oxidative stress.
  38. Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing.
  39. Natural diterpenoid eriocalyxin B covalently modifies glutathione and selectively inhibits thioredoxin reductase inducing potent oxidative stress-mediated apoptosis in colorectal carcinoma RKO cells.
  1. Pharmaceuticals (Basel). 2021 Sep 29. pii: 994. [Epub ahead of print]14(10):
    Soft Coral-Derived Dihydrosinularin Exhibits Antiproliferative Effects Associated with Apoptosis and DNA Damage in Oral Cancer Cells.
    Kun-Han Yang, Yu-Sheng Lin, Sheng-Chieh Wang, Min-Yu Lee, Jen-Yang Tang, Fang-Rong Chang, Ya-Ting Chuang, Jyh-Horng Sheu, Hsueh-Wei Chang.
      Dihydrosinularin (DHS) is an analog of soft coral-derived sinularin; however, the anticancer effects and mechanisms of DHS have seldom been reported. This investigation examined the antiproliferation ability and mechanisms of DHS on oral cancer cells. In a cell viability assay, DHS showed growth inhibition against several types of oral cancer cell lines (Ca9-22, SCC-9, OECM-1, CAL 27, OC-2, and HSC-3) with no cytotoxic side effects on non-malignant oral cells (HGF-1). Ca9-22 and SCC-9 cell lines showing high susceptibility to DHS were selected to explore the antiproliferation mechanisms of DHS. DHS also causes apoptosis as detected by annexin V, pancaspase, and caspase 3 activation. DHS induces oxidative stress, leading to the generation of reactive oxygen species (ROS)/mitochondrial superoxide (MitoSOX) and mitochondrial membrane potential (MitoMP) depletion. DHS also induced DNA damage by probing γH2AX phosphorylation. Pretreatment with the ROS scavenger N-acetylcysteine (NAC) can partly counter these DHS-induced changes. We report that the marine natural product DHS can inhibit the cell growth of oral cancer cells. Exploring the mechanisms of this cancer cell growth inhibition, we demonstrate the prominent role DHS plays in oxidative stress.
    Keywords:  DNA damage; Dihydrosinularin (DHS); MitoMP; MitoSOX; apoptosis; oral cancer; reactive oxygen species (ROS); soft coral
    DOI:  https://doi.org/10.3390/ph14100994
  2. Antioxidants (Basel). 2021 Sep 30. pii: 1559. [Epub ahead of print]10(10):
    Stimulation of ROS Generation by Extract of Warburgia ugandensis Leading to G0/G1 Cell Cycle Arrest and Antiproliferation in A549 Cells.
    Yong-Li Zhang, Gui-Lin Chen, Ye Liu, Xiao-Cui Zhuang, Ming-Quan Guo.
      Warburgia ugandensis Sprague (WU) is a traditional medicinal plant used for the treatment of various diseases, including cancer, in Africa. This study aimed to evaluate the anti-non-small cell lung cancer (NSCLC) activities of WU against A549 cells and to reveal potential molecular mechanisms. The cytotoxicity of various WU extracts was evaluated with HeLa (cervical cancer), HepG2 (liver cancer), HT-29 (colorectal cancer), and A549 (non-small cell lung cancer) cells by means of Sulforhodamine B (SRB) assay. Therein, the dimethyl carbonate extract of WU (WUD) was tested with the most potent anti-proliferative activity against the four cancer cell lines, and its effects on cell viability, cell cycle progression, DNA damage, intracellular reactive oxygen species (ROS), and expression levels of G0/G1-related proteins in A549 cells were further examined. First, it was found that WUD inhibited the proliferation of A549 cells in a time- and dose-dependent manner. In addition, WUD induced G0/G1 phase arrest and modulated the expression of G0/G1 phase-associated proteins Cyclin D1, Cyclin E1, and P27 in A549 cells. Furthermore, WUD increased the protein abundance of P27 by inhibiting FOXO3A/SKP2 axis-mediated protein degradation and also significantly induced the γH2AX expression and intracellular ROS generation of A549 cells. It was also found that the inhibitory effect of WUD on the proliferation and G0/G1 cell cycle progression of A549 cells could be attenuated by NAC, a ROS scavenger. On the other hand, phytochemical analysis of WUD with UPLC-QTOF-MS/MS indicated 10 sesquiterpenoid compounds. In conclusion, WUD exhibited remarkable anti-proliferative effects on A549 cells by improving the intracellular ROS level and by subsequently modulating the cell proliferation and G0/G1 cell cycle progression of A549 cells. These findings proved the good therapeutic potential of WU for the treatment of NSCLC.
    Keywords:  A549 cells; DNA damage; G0/G1 phase arrest; ROS; Warburgia ugandensis
    DOI:  https://doi.org/10.3390/antiox10101559
  3. Int J Mol Sci. 2021 Oct 12. pii: 10987. [Epub ahead of print]22(20):
    Reactive Oxygen Species Mediate 6c-Induced Mitochondrial and Lysosomal Dysfunction, Autophagic Cell Death, and DNA Damage in Hepatocellular Carcinoma.
    Senzhen Wang, Xiaojuan Xu, Delu Che, Ronghui Fan, Mengke Gao, Yue Cao, Chaochao Ge, Yongli Feng, Jinghua Li, Songqiang Xie, Chaojie Wang, Fujun Dai, Lei Gao, Yuxia Wang.
      Increasing the level of reactive oxygen species (ROS) in cancer cells has been suggested as a viable approach to cancer therapy. Our previous study has demonstrated that mitochondria-targeted flavone-naphthalimide-polyamine conjugate 6c elevates the level of ROS in cancer cells. However, the detailed role of ROS in 6c-treated cancer cells is not clearly stated. The biological effects and in-depth mechanisms of 6c in cancer cells need to be further investigated. In this study, we confirmed that mitochondria are the main source of 6c-induced ROS, as demonstrated by an increase in 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox fluorescence. Compound 6c-induced mitochondrial ROS caused mitochondrial dysfunction and lysosomal destabilization confirmed by absolute quantitation (iTRAQ)-based comparative proteomics. Compound 6c-induced metabolic pathway dysfunction and lysosomal destabilization was attenuated by N-acetyl-L-cysteine (NAC). iTRAQ-based comparative proteomics showed that ROS regulated the expression of 6c-mediated proteins, and treatment with 6c promoted the formation of autophagosomes depending on ROS. Compound 6c-induced DNA damage was characterized by comet assay, p53 phosphorylation, and γH2A.X, which was diminished by pretreatment with NAC. Compound 6c-induced cell death was partially reversed by 3-methyladenine (3-MA), bafilomycin (BAF) A1, and NAC, respectively. Taken together, the data obtained in our study highlighted the involvement of mitochondrial ROS in 6c-induced autophagic cell death, mitochondrial and lysosomal dysfunction, and DNA damage.
    Keywords:  DNA damage; autophagic cell death; lysosomes; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms222010987
  4. Environ Toxicol. 2021 Oct 18.
    Xanthorrhizol inhibits non-small cell carcinoma (A549) cell growth and promotes apoptosis through modulation of PI3K/AKT and NF-κB signaling pathway.
    Yong Cai, Zhaoying Sheng, Jiying Wang.
      Xanthorrhizol (XNT) is a sesquiterpenoid agent isolated from Curcuma xanthorrhiza; It is known to exhibit various pharmacological activities including anti-cancer. We investigated the anti-cell proliferative and proapoptotic effects of XNT on Non-small cell carcinoma (A549) cells were analyzed by the generation of reactive oxygen species (ROS), alteration of mitochondrial membrane potential (ΔΨm), oxidative DNA damage, and apoptosis morphological changes were explored by Hoechst and AO/EtBr staining. Our study demonstrated that XNT treatment significantly reduced the viability of A549 cells in a concentration-dependent manner. We observed that XNT-induced oxidative stress-mediated apoptotic cell death by increasing intracellular ROS generation, depleting antioxidant levels, enhancing lipid peroxidation, increased apoptotic morphological changes, and % of DNA damage on human lung cancer cells. Furthermore, we observed that the XNT induce apoptosis through inhibits phosphorylation of PI3K, AKTand inhibit NF-κBp65 transcriptional signaling activity. In addition, XNT treatment alters the ΔΨm, thereby induces apoptosis was closely coordinated with the induction of pro-apoptotic markers Bax, Bad, caspase- 3, 9 and cytochrome c, and suppression of anti-apoptotic (Bcl-2, Bcl-XL) protein expression. According to our results, XNT-inducing apoptosis in A549 cells by causing oxidative damage and modulating apoptotic signaling events. Finally, XNT-induced apoptotic cell death was confirmed by the TUNEL assay. Therefore, XNT might be used as a chemotherapeutic agent for the treatment of lung cancer.
    Keywords:  NF-κBp65; Xanthorrhizol; apoptosis; lung cancer; oxidative-stress
    DOI:  https://doi.org/10.1002/tox.23383
  5. BMB Rep. 2021 Oct 22. pii: 5445. [Epub ahead of print]
    Pulsed electromagnetic field potentiates etoposide-induced MCF-7 cell death.
    Sung-Hun Woo, Bohee Kim, Sung Hoon Kim, Byung Chul Jung, Yongheum Lee, Yoon Suk Kim.
      Etoposide is a chemotherapeutic medication used to treat various types of cancer, including breast cancer. It is established that pulsed electromagnetic field (PEMF) therapy can enhance the effects of anti-cancer chemotherapeutic agents. In this study, we investigated whether PEMFs influence the anti-cancer effects of etoposide in MCF-7 cells and determined the signal pathways affected by PEMFs. We observed that co-treatment with etoposide and PEMFs led to a decrease in viable cells compared with cells solely treated with etoposide. PEMFs elevated the etoposide-induced PARP cleavage and caspase-7/9 activation and enhanced the etoposide-induced down-regulation of survivin and up-regulation of Bax. PEMF also increased the etoposide-induced activation of DNA damage-related molecules. In addition, the reactive oxygen species (ROS) level was slightly elevated during etoposide treatment and significantly increased during co-treatment with etoposide and PEMF. Moreover, treatment with ROS scavenger restored the PEMF-induced decrease in cell viability in etoposide-treated MCF-7 cells. These results combined indicate that PEMFs enhance etoposide-induced cell death by increasing ROS induction-DNA damage-caspase-dependent apoptosis.
  6. Antioxidants (Basel). 2021 Oct 10. pii: 1588. [Epub ahead of print]10(10):
    Burmannic Acid Inhibits Proliferation and Induces Oxidative Stress Response of Oral Cancer Cells.
    Su-Ling Liu, Kun-Han Yang, Che-Wei Yang, Min-Yu Lee, Ya-Ting Chuang, Yan-Ning Chen, Fang-Rong Chang, Chung-Yi Chen, Hsueh-Wei Chang.
      Burmannic acid (BURA) is a new apocarotenoid bioactive compound derived from Indonesian cinnamon; however, its anticancer effect has rarely been investigated in oral cancer cells. In this investigation, the consequences of the antiproliferation of oral cancer cells effected by BURA were evaluated. BURA selectively suppressed cell proliferation of oral cancer cells (Ca9-22 and CAL 27) but showed little cytotoxicity to normal oral cells (HGF-1). In terms of mechanism, BURA perturbed cell cycle distribution, upregulated mitochondrial superoxide, induced mitochondrial depolarization, triggered γH2AX and 8-hydroxy-2-deoxyguanosine DNA damage, and induced apoptosis and caspase 3/8/9 activation in oral cancer cells. Application of N-acetylcysteine confirmed oxidative stress as the critical factor in promoting antiproliferation, apoptosis, and DNA damage in oral cancer cells.
    Keywords:  DNA damage; apoptosis; burmannic acid; oral cancer; oxidative stress; spices
    DOI:  https://doi.org/10.3390/antiox10101588
  7. Cancers (Basel). 2021 Oct 09. pii: 5037. [Epub ahead of print]13(20):
    Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities.
    Maria Alba Sorolla, Ivan Hidalgo, Anabel Sorolla, Robert Montal, Ona Pallisé, Antonieta Salud, Eva Parisi.
      Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.
    Keywords:  antioxidants; clinical trials; colorectal cancer; pro-oxidants; reactive oxygen species; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13205037
  8. Cells. 2021 Oct 09. pii: 2707. [Epub ahead of print]10(10):
    Redox Control of the Dormant Cancer Cell Life Cycle.
    Bowen Li, Yichun Huang, Hui Ming, Edouard C Nice, Rongrong Xuan, Canhua Huang.
      Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells.
    Keywords:  ROS; cancer dormancy; cancer therapy; redox signaling
    DOI:  https://doi.org/10.3390/cells10102707
  9. Biomolecules. 2021 Oct 08. pii: 1485. [Epub ahead of print]11(10):
    Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells.
    Rosaria Acquaviva, Barbara Tomasello, Claudia Di Giacomo, Rosa Santangelo, Alfonsina La Mantia, Irina Naletova, Maria Grazia Sarpietro, Francesco Castelli, Giuseppe Antonio Malfa.
      Gastrointestinal cancers, particularly colorectal cancer, are mainly influenced by the dietary factor. A diet rich in fruits and vegetables can help to reduce the incidence of colorectal cancer thanks to the phenolic compounds, which possess antimutagenic and anticarcinogenic properties. Polyphenols, alongside their well-known antioxidant properties, also show a pro-oxidative potential, which makes it possible to sensitize tumor cells to oxidative stress. HO-1 combined with antioxidant activity, when overexpressed in cancer cells, is involved in tumor progression, and its inhibition is considered a feasible therapeutic strategy in cancer treatment. In this study, the effects of protocatechuic acid (PCA) on the viability of colon cancer cells (CaCo-2), annexin V, LDH release, reactive oxygen species levels, total thiol content, HO-1, γ-glutamylcysteine synthetase, and p21 expression were evaluated. PCA induced, in a dose-dependent manner, a significantly reduced cell viability of CaCo-2 by oxidative/antioxidant imbalance. The phenolic acid induced modifications in levels of HO-1, non-proteic thiol groups, γ-glutamylcysteine synthetase, reactive oxygen species, and p21. PCA induced a pro-oxidant effect in cancer cells, and the in vitro pro-apoptotic effect on CaCo-2 cells is mediated by the modulation of redox balance and the inhibition of the HO-1 system that led to the activation of p21. Our results suggest that PCA may represent a useful tool in prevention and/or therapy of colon cancer.
    Keywords:  CaCo-2; LDH leakage; annexin V; p21; phenolic acids; prooxidants; total thiol groups; γ-GCS
    DOI:  https://doi.org/10.3390/biom11101485
  10. Bioengineered. 2021 Oct 20.
    Combinative treatment of Curdione and docetaxel triggers reactive oxygen species (ROS)-mediated intrinsic apoptosis of triple-negative breast cancer cells.
    Changcheng Wang, Jia Guo, Zeng'an Wu.
      Traditional Chinese medicine Curcuma zedoary has been used for treating various diseases and cancers. However, the therapeutic effect of Curdione, one of its major components in triple negative breast cancer (TNBC) is still obscure. This study is aimed to explore whether combination of Curdione and docetaxel (DTX) could strengthen the DTX-induced pro-apoptotic effects in TNBC cells and identify its involved signaling pathways. In this study, combination of Curdione and DTX intensified the inhibited MDA-MB-468 cell proliferation and increased cell apoptosis caused by DTX treatment alone. Moreover, the combinative treatment of Curdione and DTX synergistically potentiated DTX-induced cell apoptosis by triggering reactive oxygen species (ROS) generation. Co-treatment with NAC (ROS inhibitor) could mostly block the effects induced by combination of Curdione and DTX. SB203580 (p38 inhibitor) or SC-79 (Akt activator) could partly reverse the effects induced by co-treatment, indicating that mitogen-actived protein kinases (MAPKs) and the phosphatidylinositol 3-kinases (PI3K) /Akt signaling pathway were involved in the co-treatment induced ROS-mediated cell apoptosis. To sum up, combination of Curdione and DTX enhanced the chemotherapeutic efficacy on MDA-MB-468 cells by triggering ROS-mediated cell apoptosis via MAPKs and PI3K/Akt signaling pathways. Curdione combined with DTX might have potentials application as the therapeutic strategy for TNBC.
    Keywords:  Curdione; chemo-sensitization; docetaxel; reactive oxygen species (ROS); triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1080/21655979.2021.1994737
  11. Antioxidants (Basel). 2021 Sep 27. pii: 1531. [Epub ahead of print]10(10):
    The Cytotoxicity of Doxorubicin Can Be Accelerated by a Combination of Hyperthermia and 5-Aminolevulinic Acid.
    Hiromi Kurokawa, Hirofumi Matsui.
      Chemotherapy is cytotoxic to various cancer cells and as well as normal cells. Thus, treatments that demonstrate selective cytotoxicity for cancer cells are desired. The combination of chemotherapy and other cancer therapies can show synergic cytotoxicity, which may be a clue to the nature of the involved cancer cellar-specific damage. We previously reported a phenomenon whereby mitochondrial reactive oxygen species (mitROS) regulate the expression transporters involved in anticancer drug transport and mitROS production is increased by hyperthermia. Moreover, the uptake of 5-aminolevulinic acid (ALA) was enhanced by the increase in mitROS production. In this study, we investigated whether the combination of hyperthermia and ALA can enhance the cytotoxicity of doxorubicin. MitROS production and ALA-derived porphyrin accumulation by hyperthermia (HT) were increased in a murine breast cancer cell line. The expression of solute carrier 15A1 (SLC15A1) upregulated and an ATP-binding cassette subfamily G member 2 (ABCG2) downregulated by HT. Since SLC15A1 is an accumulating transporter for ALA, while ABCG2 is a porphyrin efflux transporter, porphyrin accumulation was enhanced. ABCG2 is also a doxorubicin efflux transporter. Thus, ALA treatment accelerates the intracellular concentration of porphyrin, which acts as a competitive inhibitor of doxorubicin. Indeed, the amount of intracellular doxorubicin was increased by a combination of HT and ALA. The cytotoxicity of doxorubicin was also enhanced. This enhancement was observed in the human breast cancer cell line while it was not seen in normal cells. The combination of HT and ALA treatment can enhance the cancer-specific cytotoxicity of doxorubicin.
    Keywords:  5-aminolevulinic acid; doxorubicin; hyperthermia; mitochondrial reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox10101531
  12. Cell Chem Biol. 2021 Oct 20. pii: S2451-9456(21)00434-7. [Epub ahead of print]
    Screening compound libraries for H2O2-mediated cancer therapeutics using a peroxiredoxin-based sensor.
    Yining Hao, Troy F Langford, Sun Jin Moon, Kristen A Eller, Hadley D Sikes.
      Compounds that modulate H2O2 reaction networks have applications as targeted cancer therapeutics, as a subset of cancers exhibit sensitivity to this redox signal. Previous studies to identify therapeutics that induce oxidants have relied upon probes that respond to many different oxidants in cells, and thus do not report on only H2O2, a redox signal that selectively oxidizes proteins. Here we use a genetically encoded fluorescent probe for human peroxiredoxin-2 (Prx2) oxidation in screens for small-molecule compounds that modulate H2O2 pathways. We further characterize cellular responses to several compounds selected from the screen. Our results reveal that some, but not all, of the compounds enact H2O2-mediated toxicity in cells. Among them, SMER3, an antifungal, has not been reported as an oxidant-inducing drug. Several drugs, including cisplatin, that previously have been shown to induce reactive oxygen species (ROS) do not appear to oxidize Prx2, suggesting H2O2 is not among the ROS induced by those drugs.
    Keywords:  biosensor; cancer; genetically encoded H(2)O(2) specific sensor; high-throughput drug screening; oxidative stress; peroxiredoxin; reactive oxygen species; redox metabolism; redox therapeutics
    DOI:  https://doi.org/10.1016/j.chembiol.2021.09.003
  13. Antioxidants (Basel). 2021 Oct 05. pii: 1576. [Epub ahead of print]10(10):
    Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells.
    Eva Mosejová, Rebeka Bosnjakovic, Lukáš Kubala, Ondřej Vašíček.
      Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of this study was to bring new insights into the mechanism behind the effects of pseurotin D on MEC-1 cells as a representative CLL cell line, with a particular focus on selected signaling pathways important in the proliferation of cells and targeting mitochondrial metabolism. Our results showed that pseurotin D was able to significantly inhibit the proliferation of MEC-1 cells and arrested them in the G2/M cell cycle phase. In addition, pseurotin D was able to induce apoptosis. We found that all of these effects were associated with a change in mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). We showed for the first time that pseurotin D suppresses MEC-1 cell proliferation and induces apoptotic cell death via induction of the collapse of the mitochondria respiratory chain and the ROS-related caspase pathway. Our results show the pseurotins family as promising compounds which could serve as a basis for the development of new compounds in the treatment of lymphoma.
    Keywords:  apoptosis; lymphoma; mitochondrial activity; proliferation; pseurotin D; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox10101576
  14. Pharmaceutics. 2021 Oct 06. pii: 1627. [Epub ahead of print]13(10):
    Induction of Apoptosis by Isoalantolactone in Human Hepatocellular Carcinoma Hep3B Cells through Activation of the ROS-Dependent JNK Signaling Pathway.
    Min Yeong Kim, Hyesook Lee, Seon Yeong Ji, So Young Kim, Hyun Hwangbo, Shin-Hyung Park, Gi-Young Kim, Cheol Park, Sun-Hee Leem, Su Hyun Hong, Yung Hyun Choi.
      Isoalantolactone (IALT) is one of the isomeric sesquiterpene lactones isolated from the roots of Inula helenium L. IALT is known to possess various biological and pharmacological activities, but its anti-cancer mechanisms are not well understood. The aim of the present study was to investigate the anti-proliferative effects of IALT in human hepatocellular carcinoma (HCC) cells and to evaluate the potential anti-cancer mechanisms. Our results demonstrated that IALT treatment concentration-dependently suppressed the cell survival of HCC Hep3B cells, which was associated with the induction of apoptosis. IALT increased the expression of death-receptor-related proteins, activated caspases, and induced Bid truncation, subsequently leading to cleavage of poly (ADP-ribose) polymerase. In addition, IALT contributed to the cytosolic release of cytochrome c by destroying mitochondrial integrity, following an increase in the Bax/Bcl-2 expression ratio. However, IALT-mediated growth inhibition and apoptosis were significantly attenuated in the presence of a pan-caspase inhibitor, suggesting that IALT induced caspase-dependent apoptosis in Hep3B cells. Moreover, IALT activated the mitogen-activated protein kinases signaling pathway, and the anti-cancer effect of IALT was significantly diminished in the presence of a potent c-Jun N-terminal kinase (JNK) inhibitor. IALT also improved the generation of intracellular reactive oxygen species (ROS), whereas the ROS inhibitor significantly abrogated IALT-induced growth reduction, apoptosis, and JNK activation. Furthermore, ROS-dependent apoptosis was revealed as a mechanism involved in the anti-cancer activity of IALT in a 3D multicellular tumor spheroid model of Hep3B cells. Taken together, our findings indicate that IALT exhibited anti-cancer activity in HCC Hep3B cells by inducing ROS-dependent activation of the JNK signaling pathway.
    Keywords:  HCC Hep3B cells; Isoalantolactone; JNK; ROS; apoptosis
    DOI:  https://doi.org/10.3390/pharmaceutics13101627
  15. Adv Exp Med Biol. 2021 ;1329 239-251
    Roles of Fibroblasts in Microenvironment Formation Associated with Radiation-Induced Cancer.
    Tsutomu Shimura.
      In tumor tissues, activated stromal fibroblasts, termed cancer-associated fibroblasts (CAFs), exhibit similar characteristics to myofibroblasts. CAFs promote cancer cell differentiation and invasion by releasing various factors, such as growth factors, chemokines, and matrix-degrading proteases, into neighboring tumor cells. However, the roles of tumor microenvironment in case of radiation-induced carcinogenesis remain poorly understood. We recently revealed that mitochondrial oxidative stress causes tumor microenvironment formation associated with radiation-induced cancer. Repeated low-dose fractionated radiation progressively damages fibroblast mitochondria and elevates mitochondrial reactive oxygen species (ROS) levels. Excessive mitochondrial ROS activate transforming growth factor-beta (TGF-β) signaling, thereby inducing fibroblasts activation and facilitating tumor microenvironment formation. Consequently, radiation affects malignant cancer cells directly and indirectly via molecular alterations in stromal fibroblasts, such as the activation of TGF-β and angiogenic signaling. This review summarizes for the first time the roles of mitochondrial oxidative stress in microenvironment formation associated with radiation-induced cancer. This review may help us understand the risks of exposure to low-dose radiation. The cross talk between cancer cells and stromal fibroblasts contributes to the development and progression of radiation-induced cancer.
    Keywords:  Cancer-associated fibroblasts; Mitochondria; Myofibroblast; Oxidative stress; ROS; Radiation; Radiation-induced cancer; Stromal cells; TGF-β signaling; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-030-73119-9_13
  16. PLoS One. 2021 ;16(10): e0254966
    Hypoxically cultured cells of oral squamous cell carcinoma increased their glucose metabolic activity under normoxic conditions.
    Yuta Shinohara, Jumpei Washio, Yuri Kobayashi, Yuki Abiko, Keiichi Sasaki, Nobuhiro Takahashi.
      OBJECTIVE: The oxygen concentration within cancer tissue is known to be low, but is expected to increase rapidly when oxygen is supplied by angiogenesis and hematogenous metastasis, suggesting that rapid increases in oxygen levels might influence cancer cell physiology. Therefore, we investigated the effects of oxygen concentration fluctuations on the glucose metabolism of cancer cells.METHODS: The glucose metabolism of oral squamous cell carcinoma (HSC-2 and HSC-3) and normal epithelial (HaCaT) cells cultured under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions was measured using a pH-stat system under normoxic or hypoxic conditions. The acidic end-products and reactive oxygen species (ROS) generated by glucose metabolism were also measured.
    RESULTS: Under normoxic conditions, the metabolic activity of hypoxically cultured cancer cells was significantly increased, and the production of acids other than lactate was upregulated, while the normal cells did not respond to rapid increases in oxygen levels. ROS production was higher in normoxic conditions in all cells, especially the hypoxically cultured HSC-3 cells.
    CONCLUSIONS: Rapid increases in oxygen levels might enhance the glucose metabolism of hypoxically cultured cancer cells by mainly activating the TCA cycle and electron transport system, which might activate cancer cells through the ATP and ROS generation.
    DOI:  https://doi.org/10.1371/journal.pone.0254966
  17. Front Endocrinol (Lausanne). 2021 ;12 732190
    Myoglobin Protects Breast Cancer Cells Due to Its ROS and NO Scavenging Properties.
    Theresa Quinting, Anna Katharina Heymann, Anne Bicker, Theresa Nauth, Andre Bernardini, Thomas Hankeln, Joachim Fandrey, Timm Schreiber.
      Myoglobin (MB) is an oxygen-binding protein usually found in cardiac myocytes and skeletal muscle fibers. It may function as a temporary storage and transport protein for O2 but could also have scavenging capacity for reactive oxygen and nitrogen species. In addition, MB has recently been identified as a hallmark in luminal breast cancer and was shown to be robustly induced under hypoxia. Cellular responses to hypoxia are regulated by the transcription factor hypoxia-inducible factor (HIF). For exploring the function of MB in breast cancer, we employed the human cell line MDA-MB-468. Cells were grown in monolayer or as 3D multicellular spheroids, which mimic the in vivo avascular tumor architecture and physiology with a heterogeneous cell population of proliferating cells in the rim and non-cycling or necrotic cells in the core region. This central necrosis was increased after MB knockdown, indicating a role for MB in hypoxic tumor regions. In addition, MB knockdown caused higher levels of HIF-1α protein after treatment with NO, which also plays an important role in cancer cell survival. MB knockdown also led to higher reactive oxygen species (ROS) levels in the cells after treatment with H2O2. To further explore the role of MB in cell survival, we performed RNA-Seq after MB knockdown and NO treatment. 1029 differentially expressed genes (DEGs), including 45 potential HIF-1 target genes, were annotated in regulatory pathways that modulate cellular function and maintenance, cell death and survival, and carbohydrate metabolism. Of these target genes, TMEFF1, TREX2, GLUT-1, MKNK-1, and RAB8B were significantly altered. Consistently, a decreased expression of GLUT-1, MKNK-1, and RAB8B after MB knockdown was confirmed by qPCR. All three genes of interest are often up regulated in cancer and correlate with a poor clinical outcome. Thus, our data indicate that myoglobin might influence the survival of breast cancer cells, possibly due to its ROS and NO scavenging properties and could be a valuable target for cancer therapy.
    Keywords:  HIF; NO; ROS; breast cancer; hypoxia; myoglobin; tumor
    DOI:  https://doi.org/10.3389/fendo.2021.732190
  18. Antioxidants (Basel). 2021 Oct 14. pii: 1618. [Epub ahead of print]10(10):
    FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells.
    Miguel Córdova-Delgado, Sebastián Fuentes-Retamal, Charlotte Palominos, Camila López-Torres, Daniela Guzmán-Rivera, Oney Ramírez-Rodríguez, Ramiro Araya-Maturana, Félix A Urra.
      Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), Δψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells.
    Keywords:  2-oxoglutarate dehydrogenase (OGDH); AMP-activated kinase (AMPK) signaling; CPI-613; devimistat; mitocans; mitochondria; tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.3390/antiox10101618
  19. Front Bioeng Biotechnol. 2021 ;9 761218
    Nanosonosensitizers With Ultrasound-Induced Reactive Oxygen Species Generation for Cancer Sonodynamic Immunotherapy.
    Danling Cheng, Xiaoying Wang, Xiaojun Zhou, Jingchao Li.
      Immunotherapy is a promising therapeutic strategy for cancer, while it has been demonstrated to encounter the issues of low immune responses and underlying immune-related adverse events. The sonodynamic therapy (SDT) that utilizes sonosensitizers to produce reactive oxygen species (ROS) triggered by ultrasound (US) stimulation can be used to ablate tumors, which also leads to the induction of immunogenic cell death (ICD), thus achieving SDT-induced immunotherapy. Further combination of SDT with immunotherapy is able to afford enhanced antitumor immunity for tumor regression. In this mini review, we summarize the recent development of nanosonosensitizers with US-induced ROS generation for cancer SDT immunotherapy. The uses of nanosonosensitizers to achieve SDT-induced immunotherapy, combinational therapy of SDT with immunotherapy, and combinational therapy of SDT with multiple immunotherapies are briefly introduced. Furthermore, the current concerns and perspectives for the development and further clinical applications of these nanosonosensitizers for SDT-combined immunotherapy of cancer are discussed.
    Keywords:  immunotherapy; nanosonosensitizers; reactive oxygen species; sonodynamic therapy; ultrasound
    DOI:  https://doi.org/10.3389/fbioe.2021.761218
  20. J Pers Med. 2021 Sep 22. pii: 942. [Epub ahead of print]11(10):
    Berberine Photo-Activation Potentiates Cytotoxicity in Human Astrocytoma Cells through Apoptosis Induction.
    Francesca Carriero, Carolina Martinelli, Fabio Gabriele, Giulia Barbieri, Lisa Zanoletti, Gloria Milanesi, Claudio Casali, Alberto Azzalin, Federico Manai, Mayra Paolillo, Sergio Comincini.
      Photodynamic therapy (PDT) has recently attracted interest as an innovative and adjuvant treatment for different cancers including malignant gliomas. Among these, Glioblastoma (GBM) is the most prevalent neoplasm in the central nervous system. Despite conventional therapeutic approaches that include surgical removal, radiation, and chemotherapy, GBM is characterized by an extremely poor prognosis and a high rate of recurrence. PDT is a physical process that induces tumor cell death through the genesis and accumulation of reactive oxygen species (ROS) produced by light energy interaction with a photosensitizing agent. In this contribution, we explored the potentiality of the plant alkaloid berberine (BBR) as a photosensitizing and cytotoxic agent coupled with a PDT scheme using a blue light source in human established astrocytoma cell lines. Our data mainly indicated for the combined BBR-PDT scheme a potent activation of the apoptosis pathway, through a massive ROS production, a great extent of mitochondria depolarization, and the sub-sequent activation of caspases. Altogether, these results demonstrated that BBR is an efficient photosensitizer agent and that its association with PDT may be a potential anticancer strategy for high malignant gliomas.
    Keywords:  astrocytoma; glial tumor; oxidative stress; phyto-therapy
    DOI:  https://doi.org/10.3390/jpm11100942
  21. Antioxidants (Basel). 2021 Oct 13. pii: 1606. [Epub ahead of print]10(10):
    Phytochemicals from Indian Ethnomedicines: Promising Prospects for the Management of Oxidative Stress and Cancer.
    Nishat Fatima, Syed Shabihe Raza Baqri, Ahmad Alsulimani, Sharmila Fagoonee, Petr Slama, Kavindra Kumar Kesari, Shubhadeep Roychoudhury, Shafiul Haque.
      Oxygen is indispensable for most organisms on the earth because of its role in respiration. However, it is also associated with several unwanted effects which may sometimes prove fatal in the long run. Such effects are more evident in cells exposed to strong oxidants containing reactive oxygen species (ROS). The adverse outcomes of oxidative metabolism are referred to as oxidative stress, which is a staple theme in contemporary medical research. Oxidative stress leads to plasma membrane disruption through lipid peroxidation and has several other deleterious effects. A large body of literature suggests the involvement of ROS in cancer, ageing, and several other health hazards of the modern world. Plant-based cures for these conditions are desperately sought after as supposedly safer alternatives to mainstream medicines. Phytochemicals, which constitute a diverse group of plant-based substances with varying roles in oxidative reactions of the body, are implicated in the treatment of cancer, aging, and all other ROS-induced anomalies. This review presents a summary of important phytochemicals extracted from medicinal plants which are a part of Indian ethnomedicine and Ayurveda and describes their possible therapeutic significance.
    Keywords:  ROS; cancer; ethnomedicine; oxidative stress; phytochemicals
    DOI:  https://doi.org/10.3390/antiox10101606
  22. Antioxidants (Basel). 2021 Oct 14. pii: 1616. [Epub ahead of print]10(10):
    Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: Reducing Radicals to Refine Responses.
    Abdul Mannan, Zacary P Germon, Janis Chamberlain, Jonathan R Sillar, Brett Nixon, Matthew D Dun.
      Acute lymphoblastic leukaemia (ALL) is the most common cancer diagnosed in children and adolescents. Approximately 70% of patients survive >5-years following diagnosis, however, for those that fail upfront therapies, survival is poor. Reactive oxygen species (ROS) are elevated in a range of cancers and are emerging as significant contributors to the leukaemogenesis of ALL. ROS modulate the function of signalling proteins through oxidation of cysteine residues, as well as promote genomic instability by damaging DNA, to promote chemotherapy resistance. Current therapeutic approaches exploit the pro-oxidant intracellular environment of malignant B and T lymphoblasts to cause irreversible DNA damage and cell death, however these strategies impact normal haematopoiesis and lead to long lasting side-effects. Therapies suppressing ROS production, especially those targeting ROS producing enzymes such as the NADPH oxidases (NOXs), are emerging alternatives to treat cancers and may be exploited to improve the ALL treatment. Here, we discuss the roles that ROS play in normal haematopoiesis and in ALL. We explore the molecular mechanisms underpinning overproduction of ROS in ALL, and their roles in disease progression and drug resistance. Finally, we examine strategies to target ROS production, with a specific focus on the NOX enzymes, to improve the treatment of ALL.
    Keywords:  NADPH oxidases; acute lymphoblastic leukaemia; antioxidants; cysteine oxidation; kinase; oncogenic signalling; oxidative DNA damage; oxidative stress; phosphatase; reactive oxygen species; redox homeostasis; resistance; second messenger signalling
    DOI:  https://doi.org/10.3390/antiox10101616
  23. Cell Death Dis. 2021 Oct 22. 12(11): 986
    Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis.
    Qian Wang, Ci Xu, Qiang Fan, Haihua Yuan, Xin Zhang, Biying Chen, Renjie Cai, Yanjie Zhang, Moubin Lin, Ming Xu.
      MAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.
    DOI:  https://doi.org/10.1038/s41419-021-04302-6
  24. Mol Biol Rep. 2021 Oct 21.
    Role of NRF2 cascade in determining the differential response of cervical cancer cells to anticancer drugs: an in vitro study.
    Pushkal Sinduvadi Ramesh, Sharanya Raja, Shwethambari Harave Udayakumar, Shruthi Chandrashekar, Suma M Nataraj, Devananda Devegowda.
      BACKGROUND: Cervical cancers are usually treatable if detected in early stages by a combination of therapies. However, the prognosis of cervical cancer patients with metastasis remains unfavorable due to the fact that most of the cervical carcinomas are either resistant to anticancer drugs or show signs of relapse after initial treatment. Therefore, it is important to control the chemoresistance as it is the key to develop effective treatment options for cervical cancer.OBJECTIVE: The current study aimed at evaluating the differential responses of cervical cancer cells to anti-cancer drugs and assessed whether the differences in the expression profiles of antioxidant genes regulated by nuclear factor erythroid-2-related factor 2 (NRF2), led to the variations in the sensitivities of the cancer cells to treatment.
    METHODOLOGY: Three cervical cancer cell lines were investigated for their differences in NRF2 pathway by measuring the gene expression and enzyme activity. The differences in the sensitivity to anti-cancer drugs and variation in ROS profile was also evaluated. The addition of exogenous drugs to manipulate the intracellular ROS and its effect on NRF2 pathway genes was also investigated.
    RESULTS: HeLa and SiHa cells were more sensitive to cisplatin and oxaliplatin treatment than C33A cells. HeLa and SiHa cells had significantly lower NRF2 gene levels, NQO1 enzyme activity and basal GSH levels than C33A cells. Levels of ROS induced were higher in HeLa than C33A cells.
    CONCLUSION: Overall, the differences in the cellular levels of antioxidant regulatory genes led to the differential response of cervical cancer cells to anti-cancer drugs.
    Keywords:  Antioxidant genes; Cervical cancer; Chemoresistance; Gene expression; NRF2; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11033-021-06848-2
  25. Int J Mol Sci. 2021 Oct 19. pii: 11285. [Epub ahead of print]22(20):
    Sodium Butyrate Enhances Curcuminoids Permeability through the Blood-Brain Barrier, Restores Wnt/β-Catenin Pathway Antagonists Gene Expression and Reduces the Viability of Glioblastoma Cells.
    Aleksandra Majchrzak-Celińska, Robert Kleszcz, Anna Stasiłowicz-Krzemień, Judyta Cielecka-Piontek.
      Glioblastoma (GBM) is an extremely aggressive brain tumor awaiting novel, efficient, and minimally toxic treatment. Curcuminoids (CCM), polyphenols from Curcuma longa, and sodium butyrate (NaBu), a histone deacetylase inhibitor naturally occurring in the human body, await elucidation as potential anti-GBM agents. Thus, the aim of this study was to analyze CCM and NaBu both separately and as a combination treatment using three GBM cell lines. MTT was used for cytotoxicity evaluation, and the combination index was calculated for synergism prediction. Cell cycle, apoptosis, and reactive oxygen species (ROS) generation were analyzed using flow cytometry. DNA methylation was verified by MS-HRM and mRNA expression by qPCR. The permeability through the blood-brain barrier (BBB) and through the nasal cavity was evaluated using PAMPA model. The results of this study indicate that CCM and NaBu synergistically reduce the viability of GBM cells inducing apoptosis and cell cycle arrest. These effects are mediated via ROS generation and changes in gene expression, including upregulation of Wnt/β-catenin pathway antagonists, SFRP1, and RUNX3, and downregulation of UHRF1, the key epigenetic regulator. Moreover, NaBu ameliorated CCM permeability through the BBB and the nasal cavity. We conclude that CCM and NaBu are promising agents with anti-GBM properties.
    Keywords:  DNA methylation; apoptosis; cell cycle; curcuminoids; glioblastoma; permeability; reactive oxygen species; sodium butyrate
    DOI:  https://doi.org/10.3390/ijms222011285
  26. Pharmaceutics. 2021 Sep 26. pii: 1562. [Epub ahead of print]13(10):
    Latest Innovations and Nanotechnologies with Curcumin as a Nature-Inspired Photosensitizer Applied in the Photodynamic Therapy of Cancer.
    Laura Marinela Ailioaie, Constantin Ailioaie, Gerhard Litscher.
      In the context of the high incidence of cancer worldwide, state-of-the-art photodynamic therapy (PDT) has entered as a usual protocol of attempting to eradicate cancer as a minimally invasive procedure, along with pharmacological resources and radiation therapy. The photosensitizer (PS) excited at certain wavelengths of the applied light source, in the presence of oxygen releases several free radicals and various oxidation products with high cytotoxic potential, which will lead to cell death in irradiated cancerous tissues. Current research focuses on the potential of natural products as a superior generation of photosensitizers, which through the latest nanotechnologies target tumors better, are less toxic to neighboring tissues, but at the same time, have improved light absorption for the more aggressive and widespread forms of cancer. Curcumin incorporated into nanotechnologies has a higher intracellular absorption, a higher targeting rate, increased toxicity to tumor cells, accelerates the activity of caspases and DNA cleavage, decreases the mitochondrial activity of cancer cells, decreases their viability and proliferation, decreases angiogenesis, and finally induces apoptosis. It reduces the size of the primary tumor, reverses multidrug resistance in chemotherapy and decreases resistance to radiation therapy in neoplasms. Current research has shown that the use of PDT and nanoformulations of curcumin has a modulating effect on ROS generation, so light or laser irradiation will lead to excessive ROS growth, while nanocurcumin will reduce the activation of ROS-producing enzymes or will determine the quick removal of ROS, seemingly opposite but synergistic phenomena by inducing neoplasm apoptosis, but at the same time, accelerating the repair of nearby tissue. The latest curcumin nanoformulations have a huge potential to optimize PDT, to overcome major side effects, resistance to chemotherapy, relapses and metastases. All the studies reviewed and presented revealed great potential for the applicability of nanoformulations of curcumin and PDT in cancer therapy.
    Keywords:  cancer; curcumin; light; malignant tumors; nanomedicine; natural photosensitizer; photobiomodulation (PBM); photodynamic therapy (PDT)
    DOI:  https://doi.org/10.3390/pharmaceutics13101562
  27. Am J Cancer Res. 2021 ;11(9): 4199-4219
    Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells.
    Atikul Islam, Pei-Fang Hsieh, Pei-Fen Liu, Jou-Chun Chou, Jiunn-Wang Liao, Ming-Kun Hsieh, Pin Ju Chueh.
      Although considered a sporadic type of skin cancer, malignant melanoma has regularly increased internationally and is a major cause of cancer-associated death worldwide. The treatment options for malignant melanoma are very limited. Accumulating data suggest that the natural compound, capsaicin, exhibits preferential anticancer properties to act as a nutraceutical agent. Here, we explored the underlying molecular events involved in the inhibitory effect of capsaicin on melanoma growth. The cellular thermal shift assay (CETSA), isothermal dose-response fingerprint curves (ITDRFCETSA), and CETSA-pulse proteolysis were utilized to confirm the direct binding of capsaicin with the tumor-associated NADH oxidase, tNOX (ENOX2) in melanoma cells. We also assessed the cellular impact of capsaicin-targeting of tNOX on A375 cells by flow cytometry and protein analysis. The essential role of tNOX in tumor- and melanoma-growth limiting abilities of capsaicin was evaluated in C57BL/6 mice. Our data show that capsaicin directly engaged with cellular tNOX to inhibit its enzymatic activity and enhance protein degradation capacity. The inhibition of tNOX by capsaicin was accompanied by the attenuation of SIRT1, a NAD+-dependent deacetylase. The suppression of tNOX and SIRT1 then enhanced ULK1 acetylation and induced ROS-dependent autophagy in melanoma cells. Capsaicin treatment of mice implanted with melanoma cancer cells suppressed tumor growth by down-regulating tNOX and SIRT1, which was also seen in an in vivo xenograft study with tNOX-depleted melanoma cells. Taken together, our findings suggest that tNOX expression is important for the growth of melanoma cancer cells both in vitro and in vivo, and that inhibition of the tNOX-SIRT1 axis contributes to inducting ROS-dependent autophagy in melanoma cells.
    Keywords:  Autophagy; CETSA-pulse proteolysis; cellular thermal shift assay (CETSA); melanoma; reactive oxygen species (ROS); sirtuin 1 (silent mating type information regulation 2 homolog 1 or SIRT1); tumor-associated NADH oxidase (tNOX or ENOX2)
  28. Antioxidants (Basel). 2021 Sep 29. pii: 1553. [Epub ahead of print]10(10):
    Preclinical and Clinical Antioxidant Effects of Natural Compounds against Oxidative Stress-Induced Epigenetic Instability in Tumor Cells.
    Abdelhakim Bouyahya, Naoual El Menyiy, Loubna Oumeslakht, Aicha El Allam, Abdelaali Balahbib, Abdur Rauf, Naveed Muhammad, Elena Kuznetsova, Marina Derkho, Muthu Thiruvengadam, Mohammad Ali Shariati, Nasreddine El Omari.
      ROS (reactive oxygen species) are produced via the noncomplete reduction in molecular oxygen in the mitochondria of higher organisms. The produced ROS are placed in various cell compartments, such as the mitochondria, cytoplasm, and endoplasmic reticulum. In general, there is an equilibrium between the synthesis of ROS and their reduction by the natural antioxidant defense system, called the redox system. Therefore, when this balance is upset, the excess ROS production can affect different macromolecules, such as proteins, lipids, nucleic acids, and sugars, which can lead to an electronic imbalance than oxidation of these macromolecules. Recently, it has also been shown that ROS produced at the cellular level can affect different signaling pathways that participate in the stimulation of transcription factors linked to cell proliferation and, consequently, to the carcinogenesis process. Indeed, ROS can activate the pathway of tyrosine kinase, MAP kinase, IKK, NF-KB, phosphoinositol 3 phosphate, and hypoxia-inducible factor (HIF). The activation of these signaling pathways directly contributes to the accelerated proliferation process and, as a result, the appearance of cancer. In addition, the use of antioxidants, especially natural ones, is now a major issue in the approach to cancer prevention. Some natural molecules, especially phytochemicals isolated from medicinal plants, have now shown interesting preclinical and clinical results.
    Keywords:  bioactive compounds; cancer; epigenetic; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10101553
  29. Adv Sci (Weinh). 2021 Oct 20. e2102561
    Trojan Horse-Like Nano-AIE Aggregates Based on Homologous Targeting Strategy and Their Photodynamic Therapy in Anticancer Application.
    Yin Li, Rongyuan Zhang, Qing Wan, Rong Hu, Yao Ma, Zhiming Wang, Jianquan Hou, Weijie Zhang, Ben Zhong Tang.
      Photodynamic therapy (PDT) has become a promising candidate for cancer theranostics; however, traditional photosensitizers (PSs) usually exhibit weak fluorescence and poor reactive oxygen species (ROS) generation efficiency when aggregated. Recently, aggregation-induced emission (AIE) luminogens have shown great potential in the development of novel PSs owing to their excellent aggregation-induced ROS generation (AIG-ROS) activity. However, there are still concerns that must be addressed. In this study, two near-infrared (NIR) emitters (PI and PTI) are synthesized with AIG-ROS characteristic. PTI exhibit a valuable redder emission with more effective intersystem crossing (ISC) process than PI. The two AIE-active PSs show excellent lipid droplet (LD)-specific targeting ability. The detailed therapeutic mechanism of PDT in LDs specificity is also investigated. The mechanism of oxidation of polyunsaturated fatty acids (PUFAs) in LDs to form toxic lipid peroxides (LPOs) and thereby causing cellular ferroptosis is confirmed first. Homologous targeting is also used to achieve tumor targeting via coating PSs with active cancer cell membranes. Biomimetic aggregates exhibit good targeting ability, and an improved PDT antitumor effect via AIG-ROS activity. These findings offer a clear route to develop advanced PSs with good targeting specificity. A template has also been provided for studying the therapeutic mechanism of AIE-active PSs.
    Keywords:  aggregation-induced ROS generation; homologous targeting; photodynamic therapy; therapeutic mechanism
    DOI:  https://doi.org/10.1002/advs.202102561
  30. Antioxidants (Basel). 2021 Sep 24. pii: 1514. [Epub ahead of print]10(10):
    Crucial Role of Reactive Oxygen Species (ROS) for the Proapoptotic Effects of Indirubin Derivatives in Cutaneous SCC Cells.
    Jiaqi Zhu, Peter Langer, Claas Ulrich, Jürgen Eberle.
      Efficient drugs are needed for countering the worldwide high incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis. Indirubin derivatives represent promising candidates, but their effects in cSCC cells have not been reported before. Here, we investigated the efficacy of three indirubin derivatives (DKP-071, -073 and -184) in four cSCC cell lines. High efficacy was seen in SCL-I, SCL-II, SCC-12 and SCC-13, resulting in up to 80% loss of cell proliferation, 60% loss of cell viability and 30% induced apoptosis (10 µM). Apoptosis was further enhanced in combinations with TNF-related apoptosis-inducing ligand (TRAIL). Induction of reactive oxygen species (ROS) appeared as critical for these effects. Thus, antioxidative pretreatment completely abolished apoptosis as well as restored cell proliferation and viability. Concerning the pathways, complete activation of caspases cascades (caspases-3, -4, -6, -7, -8 and -9), loss of mitochondrial membrane potential, activation of proapoptotic PKCδ (protein kinase C delta), inhibition of STAT3 (signal transducer and activator of transcription 3), downregulation of antiapoptotic XIAP (X-linked inhibitor of apoptosis protein) and survivin as well as upregulation of the proapoptotic Bcl-2 protein Puma and the cell cycle inhibitor p21 were obtained. Importantly, all activation steps were prevented by antioxidants, thus proving ROS as a master regulator of indirubins' antitumor effects. ROS induction presently develops as an important issue in anticancer therapy.
    Keywords:  antioxidants; apoptosis; cutaneous SCC; indirubin; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/antiox10101514
  31. ACS Pharmacol Transl Sci. 2021 Oct 08. 4(5): 1689-1701
    Electron Donors Rather Than Reactive Oxygen Species Needed for Therapeutic Photochemical Reaction of Near-Infrared Photoimmunotherapy.
    Takuya Kato, Ryuhei Okada, Yuto Goto, Aki Furusawa, Fuyuki Inagaki, Hiroaki Wakiyama, Hideyuki Furumoto, Dagane Daar, Baris Turkbey, Peter L Choyke, Hideo Takakura, Osamu Inanami, Mikako Ogawa, Hisataka Kobayashi.
      Near-infrared photoimmunotherapy (NIR-PIT) employs molecularly targeted antibodies conjugated with a photoabsorbing silicon-phthalocyanine dye derivative which binds to cancer cells. Application of NIR light following binding of the antibody-photoabsorber conjugates (APCs) results in ligand release on the dye, dramatic changes in solubility of the APC-antigen complex, and rapid, irreversible cell membrane damage of cancer cells in a highly selective manner, resulting in a highly immunogenic cell death. Clinically, this process results in edema after treatment mediated by reactive oxygen species (ROS). Based on the chemical and biological mechanism of NIR-PIT cytotoxicity and edema formation, in order to minimize acute inflammatory edema without compromising therapeutic effects, l-sodium ascorbate (l-NaAA) was administered to quench harmful ROS and accelerate the ligand release reaction. l-NaAA suppressed acute edema by reducing ROS after NIR-PIT yet did not alter the therapeutic effects. NIR-PIT could be performed safely under existence of l-NaAA without side effects caused by unnecessary ROS production.
    DOI:  https://doi.org/10.1021/acsptsci.1c00184
  32. Antioxidants (Basel). 2021 Oct 13. pii: 1610. [Epub ahead of print]10(10):
    Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor.
    Reziyamu Wufuer, Zhuo Fan, Keli Liu, Yiguo Zhang.
      In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)-rather than Nrf2-is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., Nrf1α-/-, Nrf2-/-ΔTA, and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tert-butylhydroquinone (tBHQ) serving as a pro-oxidative stressor. In Nrf1α-/- cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α's function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2-/-ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of Nrf1 expression resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, whether or not it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2's functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2.
    Keywords:  Cap’n’Collar (CNC); Nrf1; Nrf2; antioxidant; basic region-leucine zipper (bZIP); oxidative stress; reactive oxygen species (ROS); redox gene regulation; tert-butylhydroquinone (tBHQ)
    DOI:  https://doi.org/10.3390/antiox10101610
  33. Cancers (Basel). 2021 Oct 09. pii: 5058. [Epub ahead of print]13(20):
    Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.
    Marcella Bonanomi, Noemi Salmistraro, Giulia Fiscon, Federica Conte, Paola Paci, Valentina Bravatà, Giusi Irma Forte, Tatiana Volpari, Manuela Scorza, Fabrizia Mastroianni, Stefano D'Errico, Elenio Avolio, Gennaro Piccialli, Anna Maria Colangelo, Marco Vanoni, Daniela Gaglio, Lilia Alberghina.
      Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
    Keywords:  CtBP2; cancer metabolic rewiring; epigenetics; metabolomics integration; transcriptomics
    DOI:  https://doi.org/10.3390/cancers13205058
  34. Molecules. 2021 Oct 14. pii: 6204. [Epub ahead of print]26(20):
    Acacetin Inhibits the Growth of STAT3-Activated DU145 Prostate Cancer Cells by Directly Binding to Signal Transducer and Activator of Transcription 3 (STAT3).
    Sun Yun, Yu-Jin Lee, Jiyeon Choi, Nam Doo Kim, Dong Cho Han, Byoung-Mog Kwon.
      Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the formation and growth of human cancer. Therefore, STAT3 is a therapeutic target for cancer drug discovery. Acacetin, a flavone present in various plants, inhibits constitutive and inducible STAT3 activation in STAT3-activated DU145 prostate cancer cells. Acacetin inhibits STAT3 activity by directly binding to STAT3, which we confirmed by a pull-down assay with a biotinylated compound and two level-free methods, namely, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). Acacetin inhibits STAT3 phosphorylation at the tyrosine 705 residue and nuclear translocation in DU145 cells, which leads to the downregulation of STAT3 target genes. Acacetin then induces apoptosis in a time-dependent manner. Interestingly, acacetin induces the production of reactive oxygen species (ROS) that are not involved in the acacetin-induced inhibition of STAT3 activation because the suppressed p-STAT3 level is not rescued by treatment with GSH or NAC, which are general ROS inhibitors. We also found that acacetin inhibits tumor growth in xenografted nude mice. These results suggest that acacetin, as a STAT3 inhibitor, could be a possible drug candidate for targeting STAT3 for the treatment of cancer in humans.
    Keywords:  STAT3 inhibitor; acacetin; antitumor; label-free methods; natural product
    DOI:  https://doi.org/10.3390/molecules26206204
  35. Antioxidants (Basel). 2021 Sep 23. pii: 1506. [Epub ahead of print]10(10):
    Baicalin Enhances Chemosensitivity to Doxorubicin in Breast Cancer Cells via Upregulation of Oxidative Stress-Mediated Mitochondria-Dependent Apoptosis.
    Mei-Yi Lin, Wan-Ting Cheng, Hui-Ching Cheng, Wan-Ching Chou, Hsiu-I Chen, Hsiu-Chung Ou, Kun-Ling Tsai.
      Doxorubicin (Dox) is an effective anthracycline anticancer drug. However, recent studies have revealed that Dox resistance is a highly critical issue, and a significant reason for treatment failure. Baicalin is a flavonoid component in the roots of Scutellaria baicalensis Georgi; however, whether baicalin can increase chemosensitivity in breast cancers is still unclear. In this study, we found that cellular apoptosis occurs when excessive intracellular ROS is generated, triggered by the dual intervention of baicalin and doxorubicin, which increases intracellular calcium [Ca2+]i concentrations. Increased [Ca2+]i concentrations decrease the mitochondrial membrane potential (△Ψm), thereby causing cellular apoptosis. Pretreatment with NAC (ROS inhibitor) or BATBA (Ca2+ chelator) reduces baicalin-induced chemosensitivity. The findings of this study demonstrate that the effect of baicalin on Dox treatment could enhance cytotoxicity toward breast cancer cells via the ROS/[Ca2+]i-mediated intrinsic apoptosis pathway-thus potentially lessening the required dosage of doxorubicin, and further exploring associated mechanisms in combined treatments for breast cancer clinical interventions in the future.
    Keywords:  ROS; apoptosis; baicalin; chemosensitivity; doxorubicin
    DOI:  https://doi.org/10.3390/antiox10101506
  36. Int J Mol Sci. 2021 Oct 14. pii: 11065. [Epub ahead of print]22(20):
    Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst.
    Sergey A Tsymbal, Anna A Moiseeva, Nikol A Agadzhanian, Svetlana S Efimova, Alina A Markova, Dmitry A Guk, Olga O Krasnovskaya, Victoria M Alpatova, Andrei V Zaitsev, Anna V Shibaeva, Victor V Tatarskiy, Marina S Dukhinova, Valentina A Ol'shevskaya, Olga S Ostroumova, Elena K Beloglazkina, Alexander A Shtil.
      Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu2+ in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2-3 orders of magnitude determined by IC50 values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1-1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2-6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu-organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu-organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu+1 complexes can generate a superoxide anion in a Fenton-like reaction Cu+1L + O2 → O2-. + Cu+2L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds.
    Keywords:  cell death; copper; drug resistance; reactive oxygen species; redox potential; tumor cells
    DOI:  https://doi.org/10.3390/ijms222011065
  37. Biomed Pharmacother. 2021 Oct 19. pii: S0753-3322(21)01097-0. [Epub ahead of print]144 112313
    Corosolic acid reduces A549 and PC9 cell proliferation, invasion, and chemoresistance in NSCLC via inducing mitochondrial and liposomal oxidative stress.
    Mingming Jin, Yue Wu, Yuqing Lou, Xiyu Liu, Yitian Dai, Wenxiao Yang, Congbiao Liu, Gang Huang.
      Corosolic acid is a pentacyclic triterpenoid isolated from Lagerstroemia speciosa, which is known to inhibit cancer cell proliferations. Whereas, the role of this compound on non-small cell lung cancer (NSCLC) cells still largely unclear. So, the aim of this study was to reveal the regulatory mechanism of corosolic acid to NSCLC. Here, we cultured A549 and PC9 cells in increasing corosolic acid concentrations, as well as treated mice with a physiologically relevant concentration of the compound, and used metabolomics analysis and high-throughput sequencing to examine its influences on cell invasion and proliferation, chemoresistance, and metastasis. We found that corosolic acid inhibited cell invasion and proliferation in vivo and in vitro, as well as increase the chemosensitivity of both cell types to cisplatin. Furthermore, we found that corosolic acid destabilized the glutathione peroxidase 2-mediated redox system, which increased mitochondrial and liposomal oxidative stress. Corosolic acid also decreased the targeting protein for TPX2 level, which inhibited PI3K/AKT signaling and induced apoptosis. In addition, the accumulation of reactive oxygen species dissociated the CCNB1/CDK1 complex and induced G2/M cell cycle arrest. Taken collectively, the data indicate that corosolic acid reduces NSCLC cell invasion and proliferation, as well as chemoresistance, by inducing mitochondrial and liposomal oxidative stress.
    Keywords:  Apoptosis; Chemoresistance; Corosolic acid; Non-small cell lung cancer; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2021.112313
  38. Br J Cancer. 2021 Oct 22.
    Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing.
    Yao Jiang, Andrew D Southam, Sandro Trova, Flavio Beke, Bader Alhazmi, Thomas Francis, Anshul Radotra, Alessandro di Maio, Mark T Drayson, Chris M Bunce, Farhat L Khanim.
      BACKGROUND: We previously demonstrated the in vitro killing of AML cells by the combination of the lipid-lowering agent bezafibrate (BEZ) and the contraceptive hormone medroxyprogesterone acetate (MPA). A phase II trial demonstrated in vivo safety and efficacy of BEZ and MPA (BaP) in elderly, relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) patients. However, we observed dose-limiting toxicities in a second trial that attempted to improve outcomes via escalation of BaP doses. Thus we sought to identify a third repurposed drug that potentiates activity of low dose BaP (BaP 0.1 mM).METHODS AND RESULTS: We demonstrate that addition of a commonly used anti-epileptic, valproic acid (VAL) to low dose BaP (BaP 0.1 mM)(VBaP) enhanced killing of AML cell lines/primary AML cells to levels similar to high dose BaP (BaP 0.5 mM). Similarly, addition of VAL to BaP 0.1 mM enhanced reactive oxygen species (ROS), lipid peroxidation and inhibition of de novo fatty acid synthesis. Overexpression of Nrf2 in K562 and KG1a completely inhibited ROS production and rescued cells from VAL/BaP 0.1 mM/VBaP killing.
    CONCLUSIONS: Given the good safety data of low-dose BaP in elderly/relapsed/refractory AML patients, and that VAL alone is well-tolerated, we propose VBaP as a novel therapeutic combination for AML.
    DOI:  https://doi.org/10.1038/s41416-021-01570-z
  39. Free Radic Biol Med. 2021 Oct 14. pii: S0891-5849(21)00761-9. [Epub ahead of print]
    Natural diterpenoid eriocalyxin B covalently modifies glutathione and selectively inhibits thioredoxin reductase inducing potent oxidative stress-mediated apoptosis in colorectal carcinoma RKO cells.
    Dongzhu Duan, Yanru Wang, Xiaojie Jin, Mi Li, Le Wang, Yunyun Yan, Jian Xiao, Peng Song, Xiaoling Wang.
      Increasing evidence suggests the significant contribution of high levels of thioredoxin reductase (TrxR) in various stages of tumorigenesis and resistance to tumor chemotherapy. Thus, inhibition of TrxR with small molecules is an attractive strategy for cancer therapy. Eriocalyxin B (EriB), a naturally occurring diterpenoid extracted from Isodon eriocalyx, has reflected potential anticancer activities through numerous pathways. Here, we describe that EriB covalently modifies GSH and selectively inhibits TrxR activity by targeting the Sec residue of the enzyme. Pharmacological inhibition of TrxR by EriB results in elevated ROS levels, reduced total GSH and thiols content, which ultimately induced potent RKO cell apoptosis mediated by oxidative stress. Importantly, EriB indicates potent synthetic lethality with GSH inhibitors, BSO, in RKO cells. In summary, our results highlight that targeting TrxR by EriB explores a novel mechanism for the biological action of EriB. This opened up a new therapeutic indication for using EriB to combat cancers.
    Keywords:  Apoptosis; Colorectal cancer; Eriocalyxin B; Oxidative stress; Redox homeostasis; Thioredoxin reductase
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.10.013
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