The role of cellular reactive oxygen species in cancer chemotherapy

Yang, Haotian; Villani, Rehan; Wang, Haolu; Simpson, Matthew J.; Roberts, Michael S.; Tang, Min; Liang, Xiaowen

doi:10.1186/s13046-018-0909-x

Cited by 622 publications

(470 citation statements)

References 75 publications

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“…26 Therefore, the quantitative monitoring of dynamic ROS levels in tumours during chemotherapy is vital for effective cancer treatment. 26 In conclusion, our results demonstrated that BNIP3 and ROS are involved in platinum-based combination chemotherapy, while chemo drug-induced autophagy may protect cancer cells from cytotoxicity. Therefore, applying autophagy inhibitors may improve the effects of combination chemotherapy in treating lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…BNIP3 C-terminal phosphorylation in chemo drug-induced cell death still warrants further investigation.The role of ROS in cancer development is paradoxical. Although elevated levels of ROS are involved in cancer progression, higher levels of ROS induced by chemotherapy result in cancer cell death 26. During the oncogenic transformation of tumour cells, persistent metabolic oxidative stress promotes genomic instability and cancer development 25.…”

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confidence: 99%

“…In the physiological condition, ROS are mainly generated from mitochondria in aerobic cellular metabolism and subsequently degraded by an antioxidant system to prevent cytotoxicity. Therefore, the quantitative monitoring of dynamic ROS levels in tumours during chemotherapy is vital for effective cancer treatment 26. Although elevated levels of ROS are involved in cancer progression, higher levels of ROS induced by chemotherapy result in cancer cell death 26.…”

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confidence: 99%

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Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Chung

Tang

et al. 2019

J Cellular Molecular Medi

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These days, cancer can still not be effectively cured because cancer cells readily develop resistance to anticancer drugs. Therefore, an effective combination of drugs with different mechanisms to prevent drug resistance has become a very important issue. Furthermore, the BH3-only protein BNIP3 is involved in both apoptotic and autophagic cell death. In this study, lung cancer cells were treated with a chemotherapy drug alone or in combination to identify the role of BNIP3 and autophagy in combination chemotherapy for treating cancer. Our data revealed that various combinational treatments of two drugs could increase cancer cell death and cisplatin in combination with rapamycin or LBH589, which triggered the cell cycle arrest at the S phase. Cells with autophagosome and pEGFP-LC3 puncta increased when treated with drugs. To confirm the role of autophagy, cancer cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA). 3-MA sensitized cancer cells to chemotherapy drug treatments. These results suggest that autophagy may be responsible for cell survival in combination chemotherapy for lung cancer. Moreover, BNIP3 was induced and localized in mitochondria when cells were treated with drugs. The transfection of a dominant negative transmembrane deletion construct of BNIP3 (BNIP3ΔTM) and treatment of a reactive oxygen species (ROS) inhibitor suppressed chemo drug-induced cell death. These results indicate that BNIP3 and ROS may be involved in combination chemo drug-induced cell death. However, chemo drug-induced autophagy may protect cancer cells from drug cytotoxicity. As a result, inhibiting autophagy may improve the effects of combination chemotherapy when treating lung cancer. K E Y W O R D S autophagy, BNIP3, combination chemotherapy, reactive oxygen species How to cite this article: Chung L-Y, Tang S-J, Wu Y-C, et al. Platinum-based combination chemotherapy triggers cancer cell death through induction of Bnip3 and ROS, but not autophagy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Chung

Tang

et al. 2019

J Cellular Molecular Medi

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“…Importantly, combining ROS-inducing agents with TKI is effective to suppress tumor growth in both STACs xenograft and PDX models, raising the possibility that adjunctive therapies designed to induce ROS accumulation might provide a potential approach to improve EGFR TKI response. Of note, non-selective ROS-inducing agents that globally increase oxidants in cancer have limited therapeutic index due to excessive toxicity in sensitive tissues such as the liver and the nervous system, and many therapeutic approaches targeting intracellular ROS levels have yielded mixed results (Chio and Tuveson, 2017; Yang et al, 2018). Given the complicated role of ROS-inducing agents in cancer therapy, more efforts are needed to verify the potential translational significance of our findings and search for specific inhibitors with less toxicity, e.g., those specifically target the BCAT1-engaged pathway other than non-selective ROS-inducing agents.…”

Section: Discussionmentioning

confidence: 99%

Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

Wang

Zhang

Ren

et al. 2019

Preprint

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26 2 SUMMARY 27 Drug resistance is a significant hindrance to effective cancer treatment. Although 28 resistance mechanisms of epidermal growth factor receptor (EGFR)-mutant cancer cells to 29 lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, 30 how cancer cells orchestrate adaptive response under sublethal drug challenge remains 31 largely unknown. Here we find that 2-hour sublethal TKI treatment elicits a transient 32 drug-tolerant state in EGFR-mutant lung cancer cells. Continuous sublethal treatment 33 reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive 34 process involves H3K9 demethylation-mediated epigenetic upregulation of branched-chain 35 amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which 36 promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. 37 Combinational treatment with TKI and ROS-inducing reagents overcomes this drug 38 resistance in preclinical mouse models. Clinical information analyses support the 39 correlation of BCAT1 expression with EGFR TKI response. Collectively, our findings reveal 40 the importance of epigenetically regulated BCAT1-engaged metabolism reprogramming in 41 TKI resistance in lung cancer. 42 HIGHLIGHTS 43 Sublethal EGFR TKI treatment induces transient drug-tolerant state and long-term 44 resistance in EGFR-mutant lung cancer cells 45 Epigenetically regulated BCAT1-mediated metabolic reprogramming orchestrates EGFR 46 TKI-induced drug resistance 47 Combinational treatment with TKI and ROS-inducing agents overcomes the drug 48 resistance induced by EGFR TKI treatment 49 50 51 Cancer cells are notorious for its strong plasticity in response to cytotoxic stress. They 52 may modulate adaptive programs to survive during therapy (Holohan et al., 2013). Upon 53 lethal EGFR TKI exposure, drug-sensitive cancer cells initially undergo drastic apoptotic 54 cell death resulting in notable tumor regression; however, the remaining drug-tolerant cells 55 can follow distinct evolutionary paths and eventually acquire resistance through mutation or 56 non-mutation mechanisms (Hata et al., 2016). However, little is known about how cancer 57 cells orchestrate their adaptive response under sublethal TKI challenge. 58 Epigenetic alterations are one of the major mechanisms underlying the adaptation of 59 cancer cells to drug exposure (Easwaran et al., 2014). Epigenetic changes such as H3K4 60 demethylation or H3K9 and H3K27 methylation has been linked to lethal EGFR TKI 61 induced resistance (Guler et al., 2017; Sharma et al., 2010). 62 Under stressful conditions, cancer cells can reprogram cellular metabolism to support 63 their malignant phenotypes including proliferation, invasion and resistance to drug therapy 64 (Vander Heiden and DeBerardinis, 2017). Recently, Aberrant branched-chain amino acids 65 (BCAAs) metabolism has recently been implicated in various human malignancies 66 including leukemia, liver cancer, pancreatic cancer and non-small c...

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“…ROS are involved in countless metabolic processes that are essential for life, including adenosine triphosphate production, response to pathogens, cellular homeostasis and cell signaling (48)(49)(50). ROS have also been postulated by many to be causally involved in chemo brain (38,51). Anthracyclines like doxorubicin have been shown to result in the production of extremely high levels of ROS (37,38,52).…”

Section: Mitochondrial Biophoton Emissionmentioning

confidence: 99%

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release

Sordillo

2020

Anticancer Res

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The majority of patients receiving chemotherapy experience post-chemotherapy cognitive impairment, sometimes referred to as "chemo brain" or "chemo fog." The cognitive impairment associated with this syndrome can be severe, and can sometimes last for many years after therapy discontinuation. Despite extensive investigations, its etiology is unknown. We argue that chemo brain results from damage to tubulin within microtubules. This damage can occur directly from tubulin inhibitors such as taxanes, epothilones or vinca alkaloids. Other chemotherapies stimulate increased mitochondrial activity and biophoton release. This results in abnormal tryptophan metabolism and excess production of neurotoxic kynurenines, which, in turn, damage microtubules.

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The role of cellular reactive oxygen species in cancer chemotherapy

Cited by 622 publications

References 75 publications

Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release

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