Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

David Murray,Razmik Mirzayans

doi:10.3390/ijms21165766

David Murray, Razmik Mirzayans

Open Access

https://doi.org/10.3390/ijms21165766

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Abstract

Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in solid tumour-derived cell lines. This is commonly manifested by an extended apoptotic threshold, with extensive apoptosis only being seen after very high/supralethal doses of such agents. The dormancy response can be associated with senescence-like features, polyploidy and/or multinucleation, depending in part on the p53 status of the cells. In most solid tumour-derived cells, dormancy represents a long-term survival mechanism, ultimately contributing to disease recurrence. This review highlights the nonlinearity of key aspects of the molecular and cellular responses to bulky DNA lesions in human cells treated with chemotherapeutic drugs (e.g., cisplatin) or ultraviolet light-C (a widely used tool for unraveling details of the DNA damage-response) as a function of the level of genotoxic stress. Such data highlight the growing realization that targeting dormant cancer cells, which frequently emerge following conventional anticancer treatments, may represent a novel strategy to prevent or, at least, significantly suppress cancer recurrence.

Highlights

Cellular and Molecular Responses to Cisplatin and ultraviolet light-C (UVC)Many preclinical anticancer drug discovery/optimization strategies are based on the assumption that there is some degree of dose-linearity in the various cellular and molecular responses to cytotoxic drugs that invoke genotoxic/oxidative stress
Similar observations were reported by Latonen et al [41]; exposure of human diploid fibroblasts to a low dose of UVC (10 J/m2), which would result in approximately 50% loss of clonogenic potential in the CF assay, primarily invoked a cell cycle arrest, whereas a high/supralethal dose (50 J/m2) resulted in approximately 60% of the cells undergoing apoptosis within 48 h based on sub-diploid DNA content, nuclear morphology and cleavage of poly (ADP-ribose) polymerase
Cancer cells would readily undergo apoptosis following treatment with low/nontoxic dosages of therapeutic drugs, and such responses are typically seen in hematologic cancers and cell lines

Summary

Introduction

Many preclinical anticancer drug discovery/optimization strategies are based on the assumption that there is some degree of dose-linearity in the various cellular and molecular responses to cytotoxic drugs that invoke genotoxic/oxidative stress. In addition to its central role in the DDR, p53 plays an important early cytoprotective role after low-moderate levels of genotoxic/oxidative stress by promoting the elimination of potentially harmful electrophilic and prooxidant species before they can cause injury to the genome and other key cellular targets It does this in part by upregulating genes with p53 response elements in their promoters that encode key cytoprotective proteins such as TIGAR (p53-induced glycolysis and apoptotic regulator) and GLS2 (glutaminase 2) [39]. Another dose-dependent cytoprotective response orchestrated largely by p53 involves the stress-inducible Nrf transcription factor that can activate numerous target genes that encode proteins with anti-electrophile/antioxidant activities [54] These include several known modulators of cisplatin activity, such as γ-glutamylcysteine synthetase (which is important in GSH synthesis), metallothioneins, Trx, TrxR, and key components of the PPC such as glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase. We will return to these high-stress proapoptotic signals later, but first, we will consider in some detail the responses of normal and cancer cells to UVC, cisplatin and its analogs such as oxaliplatin and carboplatin at the cellular level

The Apoptotic “Threshold” and Cell-Fate Decisions

Findings

Concluding Remarks