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

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.

REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks

“…Cisplatin, in chemotherapy, commonly exerts its antitumor effects via DNA damage-mediated cell death (8). However, cisplatin can induce apoptosis, senescence, and other therapeutic consequences with the specific response elicited depending on such factors as cell type, cell state, and dose (9)(10)(11)(12). Thus, the use of cisplatin is not, per se, tied to a specific biological outcome.…”

Tumor Suppressor Protein p53 and Inhibitor of Apoptosis Proteins in Colorectal Cancer—A Promising Signaling Network for Therapeutic Interventions

“…The correlation covers the upregulation of LIVIN and downregulation of p53 which is highly associated with aggressive tumor growth and metastatic spread [ 121 ]. P53’s main physiological function is to regulate the genes that control apoptosis [ 19 ]. Functionally, Survivin is an inhibitor of apoptosis protein, thus the repression of Survivin by p53 constitutes a mechanism that enables tumor cells to execute apoptosis upon induction by apoptotic stimuli.…”

“…This diversity enables multiple regulatory functions in cellular pathways but needs to be tightly controlled. In that context, a negative feedback loop via murine double minute 2 homologue (MDM2) and MDM4 controls p53-mediated transcriptional and post-transcriptional activity and keeps p53 at low levels under physiological conditions [ 19 , 20 ]. Following DNA damage, p53 is activated by post-translational modifications, e.g., phosphorylation by phosphatidylinositol 3-kinase-related kinase (PIKK)-family members ATM, ataxia telangiectasia and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) or indirect phosphorylation by ATM/ATR/DNA-PKcs substrates checkpoint kinases 1 (CHK1) and CHK2 [ 19 , 21 ].…”

“…In that context, a negative feedback loop via murine double minute 2 homologue (MDM2) and MDM4 controls p53-mediated transcriptional and post-transcriptional activity and keeps p53 at low levels under physiological conditions [ 19 , 20 ]. Following DNA damage, p53 is activated by post-translational modifications, e.g., phosphorylation by phosphatidylinositol 3-kinase-related kinase (PIKK)-family members ATM, ataxia telangiectasia and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) or indirect phosphorylation by ATM/ATR/DNA-PKcs substrates checkpoint kinases 1 (CHK1) and CHK2 [ 19 , 21 ]. These modifications result in p53 stabilization, activation and nuclear translocation, followed by p53-mediated transcription of a plethora of target genes, involved in cell cycle regulation, DNA damage repair and apoptosis [ 22 ].…”

Oxidative Stress-Dependent Synergistic Antiproliferation, Apoptosis, and DNA Damage of Ultraviolet-C and Coral-Derived Sinularin Combined Treatment for Oral Cancer Cells

“…UVC exposure shows translational potential to inhibit the proliferation of glioblastoma multiforme cancer cells [ 12 ]. The combined treatments of clinical drugs [ 13 , 14 ], chemical agents [ 15 ], or natural products [ 16 , 17 ] with UVC irradiation may improve the antiproliferation of several types of cancer cells. Moreover, UVC irradiation inhibits tumor growth in an animal model without apparent side effects [ 11 , 18 ].…”