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Redox signaling in drug-tolerant persister cells as an emerging therapeutic target.

ABSTRACT: Drug-tolerant persister (DTP) cells have attracted significant interest, given their predominant role in treatment failure. In this respect, DTP cells reportedly survive after anticancer drug exposure, and their DNA repair mechanisms are altered to enhance adaptive mutation, accounting for the emergence of drug-resistant mutations. DTP cells resume proliferation upon treatment withdrawal and are responsible for cancer relapse. Current evidence suggests that DTP cells mediate redox signaling-mediated cellular homeostasis by developing various adaptive mechanisms, especially metabolic reprogramming that promotes mitochondrial oxidative respiration and a robust antioxidant process. There is an increasing consensus that disrupting redox homeostasis by intervening with redox signaling is theoretically a promising therapeutic strategy for targeting these sinister cells. In this review, we provide a comprehensive overview of the characteristics of DTP cells and the underlying mechanisms involved in redox signaling, aiming to provide a unique perspective on potential therapeutic applications based on their vulnerabilities to redox regulation.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC9982619 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Redox signaling in drug-tolerant persister cells as an emerging therapeutic target.

Zhang Zhe Z Tan Yunhan Y Huang Canhua C Wei Xiawei X

EBioMedicine 20230222

Drug-tolerant persister (DTP) cells have attracted significant interest, given their predominant role in treatment failure. In this respect, DTP cells reportedly survive after anticancer drug exposure, and their DNA repair mechanisms are altered to enhance adaptive mutation, accounting for the emergence of drug-resistant mutations. DTP cells resume proliferation upon treatment withdrawal and are responsible for cancer relapse. Current evidence suggests that DTP cells mediate redox signaling-medi ...[more]

PMID: 36827719

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Project description:BackgroundDespite the effectiveness of chemotherapy and targeted therapy for colorectal cancer, drug resistance drives therapy failure and tumor relapse. Increasing evidence has suggested that cancer cells can enter a reversible drug-tolerant persister state to survive chemotherapy or targeted agents. However, the traits and treatable vulnerabilities of anti-colorectal cancer drug-tolerant persister cells is not yet known.MethodsIn this study, we established 5-fluorouracil and AZ628-tolerant persister cell models in two colorectal cancer cell lines, namely HCT116 and SW620, and revealed the characteristics of colorectal cancer persister cells by cell viability assay and flow cytometry. We investigated the efficacy and mechanism of ferroptosis inducers RSL3 and FIN56 on persister cells, which are glutathione peroxidase 4 inhibitors. In the xenograft mouse model, we further evaluated the inhibitory effect of RSL3 on tumor regrowth.ResultsColorectal cancer persister cells, which were enriched in the residual cancer cell population, exhibited reduced drug sensitivity, were largely quiescent and expressed high levels of stem cell-related genes and mesenchymal markers but not epithelial markers. The persister cells were more sensitive and underwent ferroptosis induced by glutathione peroxidase 4 inhibitors. Mechanistically, glutathione peroxidase 4 and ferrous iron, which are pivotal ferroptosis regulators, were upregulated in residual cells or tumors, and were hence potential therapeutic targets of persister cells. In the xenograft model, we confirmed that inhibition of glutathione peroxidase 4 restrained tumor regrowth after discontinuation of anti-cancer drug treatment. Moreover, biopsies obtained from patients with colorectal cancer undergoing neoadjuvant chemoradiotherapy revealed upregulated glutathione peroxidase 4 and ferritin heavy chain 1. High glutathione peroxidase 4 expression correlates with a worse prognosis in colorectal cancer patients.ConclusionsOur work reveals that the upregulated glutathione peroxidase 4 and ferrous iron in anti-colorectal cancer drug-tolerant persister cells were potential therapeutic targets. Glutathione peroxidase 4 inhibition combined with chemotherapy or targeted therapy may be a promising therapy for colorectal cancer.

Dataset Information

Redox signaling in drug-tolerant persister cells as an emerging therapeutic target.

Publications

Redox signaling in drug-tolerant persister cells as an emerging therapeutic target.

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