Role of Nucleotide Excision Repair in Cisplatin Resistance

Abstract

Cisplatin is a chemotherapeutic drug used for the treatment of a number of cancers. The efficacy of cisplatin relies on its binding to DNA and the induction of cytotoxic DNA damage to kill cancer cells. Cisplatin-based therapy is best known for curing testicular cancer; however, treatment of other solid tumors with cisplatin has not been as successful. Pre-clinical and clinical studies have revealed nucleotide excision repair (NER) as a major resistance mechanism against cisplatin in tumor cells. NER is a versatile DNA repair system targeting a wide range of helix-distorting DNA damage. The NER pathway consists of multiple steps, including damage recognition, pre-incision complex assembly, dual incision, and repair synthesis. NER proteins can recognize cisplatin-induced DNA damage and remove the damage from the genome, thereby neutralizing the cytotoxicity of cisplatin and causing drug resistance. Here, we review the molecular mechanism by which NER repairs cisplatin damage, focusing on the recent development of genome-wide cisplatin damage mapping methods. We also discuss how the expression and somatic mutations of key NER genes affect the response of cancer cells to cisplatin. Finally, small molecules targeting NER factors provide important tools to manipulate NER capacity in cancer cells. The status of research on these inhibitors and their implications in cancer treatment will be discussed.

The Role of Nucleotide Excision Repair in Cisplatin-Induced Peripheral Neuropathy: Mechanism, Prevention, and Treatment

“…Patients with metastatic testicular tumors have shown improved prognosis when their tumors have low XPA levels. These findings have also been shown in germ cell tumor patients in which low XPA gene expression conferred significantly better overall survival than patients with high XPA expression [ 67 ]. Therefore, selective targeting of XPA in neurons would be imperative to avoid the detrimental effects on oncologic control from systemic XPA deficiency.…”

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

“…XPC is important in DNA damage recognition by associating with RAD23B to bind cisplatin-induced intrastrand crosslinks and prevent proteasomal degradation. Binding of XPC to DNA is necessary for the recruitment of TFIIH, making it the rate-limiting step of GG-NER [ 58 ]. Studies have shown that enhanced expression of XPC increases resistance in many types of cancer [ 59 , 60 , 61 ].…”

“…Additionally, studies involving many different cancer cell lines have shown that the overexpression of XPC leads to cisplatin resistance ( Figure 2 ) while knockout of the gene enhances sensitivity. However, the relationship between XPC upregulation and resistance in cisplatin-treated tumors has not been thoroughly investigated [ 58 ]. Within TFIIH are two helicases, XPB and XPD, which are vital for NER function.…”

“…Within TFIIH are two helicases, XPB and XPD, which are vital for NER function. XPD mutations are commonly found in many human cancers, such as bladder cancer, which are sensitive to cisplatin treatment [ 58 ]. XPA is a scaffold protein involved in both GG-NER and TC-NER that is essential to proper assembly of the pre-incision complex, placing endonucleases in the right position for repair of damaged DNA.…”

Electrochemotherapy in Vulvar Cancer and Cisplatin Combined with Electroporation. Systematic Review and In Vitro Studies

“…The latter promotes the generation of reactive oxygen species leading to failure of DNA function by inhibiting DNA, RNA, and protein synthesis [ 22 ]. In addition, CSP anti-cancer activity is based on DNA lesions’ generation, produced by two different mechanisms: (1) CSP-DNA cross-links inhibit DNA replication and induce cell apoptosis; (2) CSP adducts block RNA elongation and therefore gene transcription, contributing to cell death [ 23 , 24 ]. Figure 2 summarizes the main mechanisms involved in ECT response.…”