bims-rehoca 2021-12-26 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–12–26
twenty-two papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.
Correlation between Oxidative Stress and Transforming Growth Factor-Beta in Cancers.
Cytotoxic cobalt (III) Schiff base complexes: in vitro anti-proliferative, oxidative stress and gene expression studies in human breast and lung cancer cells.
Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1.
Oridonin induces oxidative stress-mediated cancer cells apoptosis via targeting thioredoxin reductase.
Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species.
Radiosensitizer Effect of β-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.
Inhibition of Autophagy Promotes Hemistepsin A-Induced Apoptosis via Reactive Oxygen Species-Mediated AMPK-Dependent Signaling in Human Prostate Cancer Cells.
A Mitochondrial Oxidative Stress Amplifier to Overcome Hypoxia Resistance for Enhanced Photodynamic Therapy.
Acquired cancer tyrosine kinase inhibitor resistance: ROS as critical determinants.
Photothermal Conjugated Polymer Nanoparticles for Suppressing Breast Tumor Growth by Regulating TRPA1 Ion Channels.
Redox modulation by plant polyphenols targeting vitagenes for chemoprevention and therapy: Relevance to novel anti-cancer interventions and mini-brain organoid technology.
Catalase Overexpression Drives an Aggressive Phenotype in Glioblastoma.
Copper arsenite-complexed Fenton-like nanoparticles as oxidative stress-amplifying anticancer agents.
Chemotherapeutic drugs induce oxidative stress associated with DNA repair and metabolism modulation.
Proteome analysis of NRF2 inhibition in melanoma reveals CD44 up-regulation and increased apoptosis resistance upon vemurafenib treatment.
A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity.
Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy.
Engineering Oxygen-Irrelevant Radical Nanogenerator for Hypoxia-Independent Magnetothermodynamic Tumor Nanotherapy.
Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.
Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.
NOX4: a potential therapeutic target for pancreatic cancer and its mechanism.

Antioxidants (Basel). 2021 Nov 25. pii: 1881. [Epub ahead of print]10(12):

The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.

Tae Woo Kim, Seong-Gyu Ko.

  Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.

Keywords:  ER stress; JI017; Nox4; ROS; exosome

DOI:  https://doi.org/10.3390/antiox10121881
Int J Mol Sci. 2021 Dec 07. pii: 13181. [Epub ahead of print]22(24):

Correlation between Oxidative Stress and Transforming Growth Factor-Beta in Cancers.

Jinwook Chung, Md Nazmul Huda, Yoonhwa Shin, Sunhee Han, Salima Akter, Insug Kang, Joohun Ha, Wonchae Choe, Tae Gyu Choi, Sung Soo Kim.

  The downregulation of reactive oxygen species (ROS) facilitates precancerous tumor development, even though increasing the level of ROS can promote metastasis. The transforming growth factor-beta (TGF-β) signaling pathway plays an anti-tumorigenic role in the initial stages of cancer development but a pro-tumorigenic role in later stages that fosters cancer metastasis. TGF-β can regulate the production of ROS unambiguously or downregulate antioxidant systems. ROS can influence TGF-β signaling by enhancing its expression and activation. Thus, TGF-β signaling and ROS might significantly coordinate cellular processes that cancer cells employ to expedite their malignancy. In cancer cells, interplay between oxidative stress and TGF-β is critical for tumorigenesis and cancer progression. Thus, both TGF-β and ROS can develop a robust relationship in cancer cells to augment their malignancy. This review focuses on the appropriate interpretation of this crosstalk between TGF-β and oxidative stress in cancer, exposing new potential approaches in cancer biology.

Keywords:  cancer; metastasis; reactive oxygen species; transforming growth factor-beta; tumorigenesis

DOI:  https://doi.org/10.3390/ijms222413181
Biometals. 2021 Dec 22.

Cytotoxic cobalt (III) Schiff base complexes: in vitro anti-proliferative, oxidative stress and gene expression studies in human breast and lung cancer cells.

Balakrishnan Gowdhami, Yesaiyan Manojkumar, R T V Vimala, Venkatesan Ramya, Balakrishnan Karthiyayini, Balamuthu Kadalmani, Mohammad Abdulkader Akbarsha.

  Increasing cancer drug chemo-resistance, especially in the treatment of breast and lung cancers, alarms the immediate need of newer and effective anticancer drugs. Until now, chemotherapeutics based on metal complexes are considered the most effective treatment modality. In the present study, we have evaluated the cytotoxic effect of two cobalt (III) Schiff base complexes based on the leads from complex combinatorial chemistry. Cobalt (III) Schiff base complexes (Complex 3 = Co(Ph-acacen)(HA)2](ClO4) and Complex 4 = [Co(Ph-acacen)(DA)2](ClO4)] (Ph-acacen, 1-phenylbutane-1,3-dione; DA, dodecyl amine; HA, heptylamine) were evaluated against human breast cancer cell MCF-7 and lung cancer cell A549 using MTT cell viability assay, cellular morphological changes studied by Acridine Orange and Ethidium Bromide (AO/EB), Dual fluorescent staining, Hoechst staining 33248, Comet assay, Annexin V-Cy3 and 6 CFDA assay, JC-1 staining, Reactive oxygen species (ROS) assay, Immunofluorescence assay, and Real-time reverse transcription-polymerase chain reaction (RT-qPCR). Treatment of cobalt (III) Schiff base complexes (Complex 3 & 4) affected the viability of the cancer cells. The cell death induced by the complexes was predominantly apoptosis, but necrosis also occurred to a certain extent. Complex 4 produced better cytotoxic effect than complex 3, and MCF-7 cell was more responsive than A549. In that order, the complexes were more selective to cancer cell than normal cell, and more effective in overall performance than the standard drug cisplatin. Therefore, we conclude that cobalt (III) Schiff base complexes, especially complex 4, have the potential to be developed as effective drugs for treatment of cancers in general, and breast and lung cancers in particular.

Keywords:  Apoptosis; DNA damage; Immunofluorescence; RT-PCR; Reactive oxygen species

DOI:  https://doi.org/10.1007/s10534-021-00351-8
Cell Biosci. 2021 Dec 19. 11(1): 217

Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1.

Vanilla Xin Zhang, Karen Man-Fong Sze, Lo-Kong Chan, Daniel Wai-Hung Ho, Yu-Man Tsui, Yung-Tuen Chiu, Eva Lee, Abdullah Husain, Hongyang Huang, Lu Tian, Carmen Chak-Lui Wong, Irene Oi-Lin Ng.

   BACKGROUND: Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth.
METHODS: Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets.
RESULTS: In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo.
CONCLUSIONS: Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.

Keywords:  Antioxidants; Glutathione; Hepatocellular carcinoma; N-acetylcysteine; NRF2; Reactive oxygen species; Sorafenib; TMBIM1

DOI:  https://doi.org/10.1186/s13578-021-00731-0
Curr Pharm Biotechnol. 2021 Dec 17.

Oridonin induces oxidative stress-mediated cancer cells apoptosis via targeting thioredoxin reductase.

Dongzhu Duan, Xiaolu Feng, Dabo Pan, Le Wang, Yanru Wang, Xiaoling Wang.

   BACKGROUND: Thioredoxin reductase (TrxR) plays vital role in regulating cellular redox balance as well as redox-mediated signal transduction. Accumulating evidence supports that overactivation of TrxR is closely related to tumorigenesis and that targeting TrxR ablation reverses the growth of numerous malignant tumors, making TrxR a promising target for cancer chemotherapy. Thus, the discovery and development of molecules as promising anticancer agents that target TrxR is of great significance. Oridonin was shown to inhibit TrxR activity, but the detailed cellular mechanism is largely unknown.
OBJECTIVE: The study investigated the mechanism of action and underlying inhibitory properties of oridonin on TrxR in HeLa cells.
METHODS: A covalent docking was performed to reveal the possible interaction between oridonin and TrxR by Schrödinger Software Suite. TrxR activity was determined by 5,5'-dithiobis-2-nitrobenzoic acid reduction assay and endpoint insulin reduction assay. Sulforhodamine B and colony formation assay were employed to assess the viability and growth of cells. Reactive oxygen species level was measured by probe 2', 7'-dichlorfluorescein diacetate, and dihydroethidium. Hoechst 33342 staining, caspase 3 activation, and fluorescein-5-isothiocyanate-conjugated Annexin V and propidium iodide double staining were used to evaluate apoptosis.
RESULTS: Here, we reported the oridonin as a potent inhibitor of TrxR. Inhibition of TrxR results in a decrease of thiols content and total glutathione elevates reactive oxygen species levels, and finally promotes oxidative stress-mediated apoptosis of cancer cells.
CONCLUSION: Targeting TrxR by oridonin discloses a novel molecular mechanism underlying the biological action of oridonin and sheds light on developing oridonin as a potential tumor therapeutic agent.

Keywords:  Oridonin; apoptosis; chemotherapy; oxidative stress; redox regulation; thioredoxin reductase

DOI:  https://doi.org/10.2174/1389201023666211217151955
Antioxidants (Basel). 2021 Nov 25. pii: 1883. [Epub ahead of print]10(12):

Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species.

Yen-Po Chen, Po-Chang Shih, Chien-Wei Feng, Chang-Cheng Wu, Kuan-Hao Tsui, You-Hsien Lin, Hsiao-Mei Kuo, Zhi-Hong Wen.

  Most ovarian cancer (OC) patients are diagnosed with stage III or higher disease, resulting in a poor prognosis. Currently, paclitaxel combined with carboplatin shows the best treatment outcome for OC. However, no effective drug is available for patients that do not respond to treatment; thus, new drugs for OC are needed. We evaluated the antimicrobial peptide, pardaxin, in PA-1 and SKOV3 cells. Pardaxin induced apoptosis as determined by MTT and TUNEL assays, as well as activation of caspases-9/3, Bid, t-Bid, and Bax, whereas Bcl-2 was downregulated. The IC50 values for pardaxin were 4.6-3.0 μM at 24 and 48 h. Mitochondrial and intracellular reactive oxygen species (ROS) were overproduced and associated with disrupted mitochondrial membrane potential and respiratory capacity. Additionally, the mitochondrial network was fragmented with downregulated fusogenic proteins, MFN1/2 and L-/S-OPA1, and upregulated fission-related proteins, DRP1 and FIS1. Autophagy was also activated as evidenced by increased expression of autophagosome formation-related proteins, Beclin, p62, and LC3. Enhanced mitochondrial fragmentation and autophagy indicate that mitophagy was activated. ROS-induced cytotoxicity was reversed by the addition of N-acetylcysteine, confirming ROS overproduction as a contributor. Taken together, pardaxin demonstrated promising anticancer activity in OC cells, which warrants further preclinical development of this compound.

Keywords:  apoptosis; autophagosome; mitochondria; mitochondrial membrane potential; mitophagy; natural product; ovarian cancer; oxidative phosphorylation; pardaxin; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox10121883
Int J Mol Sci. 2021 Dec 16. pii: 13514. [Epub ahead of print]22(24):

Radiosensitizer Effect of β-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.

Jin-Hee Kwon, Na-Gyeong Lee, A-Ram Kang, Jie-Young Song, Sang-Gu Hwang, Hong-Duck Um, Joon Kim, Jong Kuk Park.

  β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Keywords:  ROS; apoptosis; colorectal cancer; radiosensitizer; topoisomerase inhibitor; β-apopicropodophyllin

DOI:  https://doi.org/10.3390/ijms222413514
Biomolecules. 2021 Dec 01. pii: 1806. [Epub ahead of print]11(12):

Inhibition of Autophagy Promotes Hemistepsin A-Induced Apoptosis via Reactive Oxygen Species-Mediated AMPK-Dependent Signaling in Human Prostate Cancer Cells.

Kwang-Youn Kim, Un-Jung Yun, Seung-Hee Yeom, Sang-Chan Kim, Hu-Jang Lee, Soon-Cheol Ahn, Kwang-Il Park, Young-Woo Kim.

  Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.

Keywords:  AMPK; Hemistepsin A; ROS; apoptosis; autophagy; prostate cancer

DOI:  https://doi.org/10.3390/biom11121806
Small Methods. 2021 Sep;5(9): e2100581

A Mitochondrial Oxidative Stress Amplifier to Overcome Hypoxia Resistance for Enhanced Photodynamic Therapy.

Ping Dong, Jialing Hu, Shuyi Yu, Yizhuo Zhou, Tianhui Shi, Yun Zhao, Xiuyuan Wang, Xiaoqing Liu.

  Hypoxia-induced resistance to tumor treatment restricts further development of photodynamic therapy. Instead of simple reoxygenation to relieve hypoxia in traditional therapeutic approaches, a mitochondria-targeted reactive oxygen species (ROS) amplifier is constructed to reverse hypoxia resistance and enhance tumor sensitivity to hypoxia-resistant photodynamic therapy. Mesoporous silica nanoparticles are modified with triphenylphosphine to enhance its blood circulation and endow it with mitochondria-targeted specificity. α-Tocopherol succinate and indocyanine green are loaded in mitochondria-targeted mesoporous silica nanoparticles to reduce innate oxygen consumption by blocking mitochondrial respiration chain, leading to endogenous mitochondrial ROS burst and imaging-guided photodynamic therapy. This mitochondria-targeted oxidative stress amplifier not only disrupts mitochondrial redox homeostasis and triggers long-term high oxidative stress but also makes tumor more sensitive to hypoxia-resistant photodynamic therapy. The imaging-guided ROS amplifier confirms the feasibility and effectiveness of both in vitro and in vivo anticancer performance, suggesting a promising clinical strategy in hypoxia-related tumor treatment.

Keywords:  hypoxia resistance; mitochondria; photodynamic therapy; reactive oxygen species burst; respiration inhibition

DOI:  https://doi.org/10.1002/smtd.202100581
Signal Transduct Target Ther. 2021 Dec 24. 6(1): 437

Acquired cancer tyrosine kinase inhibitor resistance: ROS as critical determinants.

Sander Bekeschus.

DOI: https://doi.org/10.1038/s41392-021-00844-5
Adv Healthc Mater. 2021 Dec 22. e2102506

Photothermal Conjugated Polymer Nanoparticles for Suppressing Breast Tumor Growth by Regulating TRPA1 Ion Channels.

Boying Li, Shuxi Ren, Dong Gao, Ning Li, Manman Wu, Hongbo Yuan, Mei Zhou, Chengfen Xing.

  Cancer cells survive by relying on oxidative stress defense against the accumulation of reactive oxygen species (ROS) during tumor formation. ROS sensitive TRPA1 ion channels are overexpressed in breast cancer cells and induce a large influx of Ca2+ which upregulates anti-apoptotic pathway to lead breast cancer cells to produce oxidative stress defense and enhance the resistance to ROS related chemotherapy. Targeting and inhibiting the TRPA1 ion channels are critical for breaking down the oxidative stress defense system and overcome cellular resistance. Here, near-infrared (NIR) light responsive conjugated polymer nanoparticles were designed and prepared to promote apoptosis of breast cancer cells, reduce cell drug resistance and suppress tumor growth through the remote and precise regulation of TRPA1 ion channels. Upon 808 nm laser irradiation, the nanoparticles block the formation of Ca2+ /CaM complex and regulated the content of MCL-1 protein. Especially, the nanoparticles overcome drug resistance of cancer cells, therefore accelerating apoptosis of cancer cells and suppressing tumor growth in mice. Compared with carboplatin, the volume of tumor induced by NPs-H decreased by 54.1%. This work provides a strategy to disrupt oxidative stress defense system and downregulate the anti-apoptotic signaling pathway in cancer cells. This article is protected by copyright. All rights reserved.

Keywords:  TRPA1 ion channels; drug resistance; oxidative stress tolerance; photothermal conjugated polymer nanoparticles

DOI:  https://doi.org/10.1002/adhm.202102506
Free Radic Biol Med. 2021 Dec 17. pii: S0891-5849(21)01119-9. [Epub ahead of print]

Redox modulation by plant polyphenols targeting vitagenes for chemoprevention and therapy: Relevance to novel anti-cancer interventions and mini-brain organoid technology.

Maria Scuto, Maria Laura Ontario, Angela Trovato Salinaro, Isabella Caligiuri, Francesco Rampulla, Vincenzo Zimbone, Sergio Modafferi, Flavio Rizzolio, Vincenzo Canzonieri, Edward J Calabrese, Vittorio Calabrese.

  The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects which depend on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages and inhibit its progression. Lastly, we discussed innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis from basic cancer research to clinical practice as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain as well as test drug toxicity and drive personalized and precision medicine in brain cancer.

Keywords:  Brain tumors; Chemoprevention; Hormesis; Mini-brain cancer organoids; Nanoparticles; Oxidative stress; Polyphenols; Vitagenes

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.267
Antioxidants (Basel). 2021 Dec 14. pii: 1988. [Epub ahead of print]10(12):

Catalase Overexpression Drives an Aggressive Phenotype in Glioblastoma.

Susanne Flor, Claudia R Oliva, Md Yousuf Ali, Kristen L Coleman, Jeremy D Greenlee, Karra A Jones, Varun Monga, Corinne E Griguer.

  Glioblastoma remains the deadliest form of brain cancer, largely because these tumors become resistant to standard of care treatment with radiation and chemotherapy. Intracellular production of reactive oxygen species (ROS) is necessary for chemo- and radiotherapy-induced cytotoxicity. Here, we assessed whether antioxidant catalase (CAT) affects glioma cell sensitivity to temozolomide and radiation. Using The Cancer Genome Atlas database, we found that CAT mRNA expression is upregulated in glioma tumor tissue compared with non-tumor tissue, and the level of expression negatively correlates with the overall survival of patients with high-grade glioma. In U251 glioma cells, CAT overexpression substantially decreased the basal level of hydrogen peroxide, enhanced anchorage-independent cell growth, and facilitated resistance to the chemotherapeutic drug temozolomide and ionizing radiation. Importantly, pharmacological inhibition of CAT activity reduced the proliferation of glioma cells isolated from patient biopsy samples. Moreover, U251 cells overexpressing CAT formed neurospheres in neurobasal medium, whereas control cells did not, suggesting that the radio- and chemoresistance conferred by CAT may be due in part to the enrichment of glioma stem cell populations. Finally, CAT overexpression significantly decreased survival in an orthotopic mouse model of glioma. These results demonstrate that CAT regulates chemo- and radioresistance in human glioma.

Keywords:  catalase; glioblastoma multiforme; hydrogen peroxide; radiation; reactive oxygen species (ROS); temozolomide

DOI:  https://doi.org/10.3390/antiox10121988
J Control Release. 2021 Dec 16. pii: S0168-3659(21)00669-6. [Epub ahead of print]341 646-660

Copper arsenite-complexed Fenton-like nanoparticles as oxidative stress-amplifying anticancer agents.

Giuk Lee, Chan Woo Kim, Jeong Ryul Choi, Kyung Hyun Min, Hong Jae Lee, Kyu Hwan Kwack, Hyeon-Woo Lee, Jae-Hyung Lee, Seo Young Jeong, Kiyuk Chang, Sang Cheon Lee.

  We report copper(II) arsenite (CuAS)-integrated polymer micelles (CuAS-PMs) as a new class of Fenton-like catalytic nanosystem that can display reactive oxygen species (ROS)-manipulating anticancer therapeutic activity. CuAS-PMs were fabricated through metal-catechol chelation-based formation of the CuAS complex on the core domain of poly (ethylene glycol)-b-poly(3,4-dihydroxy-L-phenylalanine) (PEG-PDOPA) copolymer micelles. CuAS-PMs maintained structural robustness under serum conditions. The insoluble state of the CuAS complex was effectively retained at physiological pH, whereas, at endosomal pH, the CuAS complex was ionized to release arsenite and cuprous Fenton catalysts (Cu+ ions). Upon endocytosis, CuAS-PMs simultaneously released hydrogen peroxide (H2O2)-generating arsenite and Fenton-like reaction-catalyzing Cu+ ions in cancer cells, which synergistically elevated the level of highly cytotoxic hydroxyl radicals (•OH), thereby preferentially killing cancer cells. Animal experiments demonstrated that CuAS-PMs could effectively suppress the growth of solid tumors without systemic in vivo toxicity. The design rationale of CuAS-PMs may provide a promising strategy to develop diverse oxidative stress-amplifying agents with great potential in cancer-specific therapy.

Keywords:  Arsenic trioxide; Cancer therapy; Fenton reaction; Hydroxyl radical; Oxidative stress; Polymer micelle

DOI:  https://doi.org/10.1016/j.jconrel.2021.12.016
Life Sci. 2021 Dec 16. pii: S0024-3205(21)01229-7. [Epub ahead of print]289 120242

Chemotherapeutic drugs induce oxidative stress associated with DNA repair and metabolism modulation.

Yujie Zhang, Chunyang Ding, Wenkang Zhu, Xinyu Li, Techang Chen, Qingxi Liu, Sa Zhou, Tong-Cun Zhang, Wenjian Ma.

  Bulky DNA damage inducing chemotherapeutic cancer drugs such as cisplatin (CIS) and doxorubicin (DOX) are commonly used in the treatment of a variety of cancers. However, they often cause multi-organ toxicity, and the mechanisms underlying are not clear. Using cellular model, the present study showed that persistent endogenous reactive oxygen species (ROS) were stimulated after a single dose short treatment with CIS and DOX. ROS level correlated with the formation of DNA double-strand breaks (DSBs). Knockdown BRCA1, a key player involved in homologous recombination (HR), enhanced ROS accumulation. Whereas knockdown DNA-PKcs and overexpress BRCA1 to inhibit nonhomologous end-joining (NHEJ) repair pathway and restore HR can partially suppress ROS levels. These data indicated that ROS production is associated with DSB formation and repair which is likely a downstream event of DNA repair. Further studies showed that knockdown DNA repair regulators PP2A but not ATM, could partially reduce ROS too. The induction of ROS affected the level of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Collectively, the present study reveals that DNA repair associated metabolism change and oxidative stress may be a direct cause of the severe side effects associated with genotoxic chemotherapy cancer drugs.

Keywords:  Chemotherapy; Cisplatin; DNA repair; Doxorubicin; Oxidative stress

DOI:  https://doi.org/10.1016/j.lfs.2021.120242
Cancer Med. 2021 Dec 23.

Proteome analysis of NRF2 inhibition in melanoma reveals CD44 up-regulation and increased apoptosis resistance upon vemurafenib treatment.

Hans Peter Weitzenböck, Anna Gschwendtner, Christoph Wiesner, Maren Depke, Frank Schmidt, Franz Trautinger, Markus Hengstschläger, Harald Hundsberger, Mario Mikula.

  Malignant melanoma is the deadliest form of skin cancer and NRF2 has been proposed as a main regulator of tumor cell malignancy. Still the mechanisms how NRF2 is contributing to melanoma progression are incompletely understood. Here we analyzed the effects of either NRF2 induction or depletion, and we also quantified changes on the whole cell proteome level. Our results showed that inhibition of NRF2 leads to a loss of reactive oxygen species protection, but at the same time to an induction of an epithelial mesenchymal transition (EMT) phenotype and an up-regulation of the stem cell marker CD44. Additionally, cells devoid of NRF2 showed increased cell viability after treatment with a MYC and a BRAF inhibitor. Importantly, survival upon vemurafenib treatment was dependent on CD44 expression. Finally, analysis of archival melanoma patient samples confirmed a vice versa relationship of NRF2 and CD44 expression. In summary, we recorded changes in the proteome after NRF2 modulation in melanoma cells. Surprisingly, we identified that NRF2 inhibition lead to induction of an EMT phenotype and an increase in survival of cells after apoptosis induction. Therefore, we propose that it is important for future therapies targeting NRF2 to consider blocking EMT promoting pathways in order to achieve efficient tumor therapy.

Keywords:  anti-oxidant response; combination therapy; malignant melanoma; redox homeostasis

DOI:  https://doi.org/10.1002/cam4.4506
J Nanobiotechnology. 2021 Dec 20. 19(1): 441

A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity.

Yawei Li, Qing Pei, Baiji Cui, Hongmei Zhang, Liu Han, Wenqing Li, Wenhe Zhu, Xianmin Feng, Zhigang Xie.

  Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug.

Keywords:  Antitumor activity; Dihydroartemisinin; Dimeric nanoprodrug; PI3K/AKT/HIF-1α signaling pathway; Redox-responsive

DOI:  https://doi.org/10.1186/s12951-021-01200-z
ACS Nano. 2021 Dec 20.

Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy.

Shuang Bai, Zhixiang Lu, Yonghe Jiang, Xiaoxiao Shi, Dazhuang Xu, Yesi Shi, Gan Lin, Chao Liu, Yang Zhang, Gang Liu.

  Current oxidative stress amplifying strategies for immunogenic cell death (ICD) promotion are mainly restricted to immune tolerance induced by adaptive cellular antioxidation, limited tumor-selectivity, and tumoral immunosuppression. Herein, a facile and efficient scenario of genetically engineering transferrin-expressing cell membrane nanovesicle encapsulated IR820-dihydroartemisinin nanomedicine (Tf@IR820-DHA) was developed to boost a-PD-L1-mediated immune checkpoint blocking (ICB) via synergetic triple stimuli-activated oxidative stress-associated ICD. We demonstrate that the engineered transferrin of Tf@IR820-DHA has excellent tumor targeting and Fe(III)-loading properties and thus delivered Fe(III) and IR820-DHA nanoparticles (NPs) to the lesion location effectively. We found that the self-carrying Fe(III)-mediated programmable catalysis of DHA and glutathione (GSH) depletion generated plenty of reactive oxygen species (ROS). Moreover, DHA also acted as an immunomodulator to decrease the number of T regulatory cells, thereby remodeling the tumor immune microenvironment and achieving double T cell activation. Furthermore, the IR820 molecule served as a competent sonosensitizer to produce ROS under ultrasound activation and guide precise immunotherapy via fluorescent/photoacoustic (FL/PA) imaging. Through its three-pronged delivery of stimuli-activated oxidative stress (DHA-induced chemodynamic therapy, catalysis-conferred GSH depletion, and IR820-mediated sonodynamic therapy), Tf@IR820-DHA caused high levels of targeted ICD. This significantly increased the proportions of IFN-γ-secreting T cells (CD4+ T and CD8+ T) and enhanced a-PD-L1-mediated ICB against primary and distant tumors, which represents a promising approach for cancer nanoimmunotherapy.

Keywords:  chemodynamic therapy; engineering nanovesicle; hepatocellular carcinoma; immunogenic cell death; oxidative stress amplification; sonodynamic therapy

DOI:  https://doi.org/10.1021/acsnano.1c08619
Small Methods. 2021 Apr;5(4): e2001087

Engineering Oxygen-Irrelevant Radical Nanogenerator for Hypoxia-Independent Magnetothermodynamic Tumor Nanotherapy.

Yujia Shen, Caihong Dong, Huijing Xiang, Cuixian Li, Fan Zhuang, Yixin Chen, Qing Lu, Yu Chen, Beijian Huang.

  Tumor hypoxia substantially lowers the treatment efficacy of oxygen-relevant therapeutic modalities because the production of reactive oxygen species in oxygen-relevant anticancer modalities is highly dependent on oxygen level in tumor tissues. Here a distinctive magnetothermodynamic anticancer strategy is developed that takes the advantage of oxygen-irrelevant free radicals produced from magnetothermal decomposable initiators for inducing cancer-cell apoptosis in vitro and tumor suppression in vivo. Free-radical nanogenerator is constructed through in situ engineering of a mesoporous silica coating on the surface of superparamagnetic Mn and Co-doped nanoparticles (MnFe2 O4 @CoFe2 O4 , denoted as Mag) toward multifunctionality, where mesoporous structure provides reservoirs for efficient loading of initiators and the Mag core serves as in situ heat source under alternating magnetic field (AMF) actuation. Upon exposure to an exogenous AMF, the magnetic hyperthermia effect of superparamagnetic core lead to the rapid decomposition of the loaded/delivered initiators (AIPH) to produce oxygen-irrelevant free radicals. Both the magnetothermal effect and generation of toxic free radicals under AMF actuation are synergistically effective in promoting cancer-cell death and tumor suppression in the hypoxic tumor microenvironment. The prominent therapeutic efficacy of this radical nanogenerator represents an intriguing paradigm of oxygen-irrelevant nanoplatform for AMF-initiated synergistic cancer treatment.

Keywords:  free radicals; magnetic hyperthermia; magnetothermodynamic therapy; nanomedicine; oxygen-irrelevant

DOI:  https://doi.org/10.1002/smtd.202001087
Biomedicines. 2021 Dec 18. pii: 1942. [Epub ahead of print]9(12):

Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.

Elisabetta Iessi, Rosa Vona, Camilla Cittadini, Paola Matarrese.

  In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.

Keywords:  OXPHOS; acidity; anticancer therapy; cancer cell metabolism; cell death; chemoresistance; glucose; glycolysis; oxidative metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines9121942
Int J Mol Sci. 2021 Dec 14. pii: 13435. [Epub ahead of print]22(24):

Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.

Chia-Lin Chen, Ching-Yu Lin, Hsing-Jien Kung.

  Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.

Keywords:  OXPHOS; cancer therapy; mitochondria

DOI:  https://doi.org/10.3390/ijms222413435
J Transl Med. 2021 Dec 20. 19(1): 515

NOX4: a potential therapeutic target for pancreatic cancer and its mechanism.

Yawei Bi, Xiao Lei, Ningli Chai, Enqiang Linghu.

  Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven isoforms of NOX family, which is upregulated in pancreatic cancer cell, mouse model of pancreatic cancer and human pancreatic cancer tissue. NOX4 is a constitutively active enzyme that primarily produces hydrogen peroxide, which exhibits completely different properties from other subtypes of NOX family. More importantly, recent studies illuminate that NOX4 promotes pancreatic cancer occurrence and development in different ways. This review summarizes the potential roles and its mechanism of NOX4 in pancreatic cancer and explores NOX4 as the potential therapeutic target in pancreatic cancer.

Keywords:  NADPH Oxidase 4; Pancreatic cancer; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12967-021-03182-w