Abstract
Simple SummaryCisplatin is successfully used for the treatment of various solid cancers. Unfortunately, it shows no activity in colorectal cancer. The resistance phenotype of colorectal cancer cells is mainly caused by alterations in p53-controlled DNA damage signaling and/or defects in the cellular mismatch repair pathway. Improvement of platinum-based chemotherapy in cisplatin-unresponsive cancers, such as colorectal cancer, might be achieved by newly designed cisplatin analogues, which retain activity in unresponsive tumor cells. Moreover, a combination of cisplatin with biochemical modulators of DNA damage signaling might sensitize cisplatin-resistant tumor cells to the drug, thus providing another strategy to improve cancer therapy.Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.
Highlights
Futile repair or mismatch repair (MMR) protein triggered pro-death DNA damage signaling are toxic events as demonstrated in various MMR deficient tumor cell lines derived from colorectal cancer, endometrial carcinoma, embryonic kidney, and ovarian carcinoma, which were found to be more tolerant to cisplatin [57,72,73]
The most pronounced effect on cisplatin activity in colorectal cancer cells is observed for the loss of p53-mediated DNA damage response combined with a defect in MMR [18,118,119]
With regards to colorectal cancer, cisplatin resistance is mainly caused by disruption of p53-mediated DNA damage response and/or loss of MMR function
Summary
DNA damage response is the In tumor suppressor protein p53, damage, which is phosactivate various transduction pathways either phorylated and signal activated upon treatment with which cisplatin [13].induce cell cycle arrest and facilitate DNA repair or trigger apoptosis and cell death [11,12]. Cisplatin resistance in tumor cells is frequently observed and might be either intrinin vitro models of cisplatin resistant tumor cell lines and include changes in drug transport sic to the tumor, as it is the case for pancreatic and colorectal carcinoma or might develop leading to reduced drug accumulation, enhanced drug detoxification by thiol-containing during courses of therapy, as observed, for example, for ovarian cancer [11] Potential molecules, such as glutathione and metallothionein, altered DNA repair mechanisms, mechanisms underlying tumor cell resistance have been identified in various in vitro namely nucleotide excision repair (NER), ICL repair and DNA mismatch repair (MMR), models of cisplatin resistant tumor cell lines and include changes in drug transport leadand alterations in the signal transduction pathways, which in turn will allow cancer ing to reduced drug accumulation, enhanced drug detoxification by thiol-containing molcells to evade cisplatin-induced cell death [14,15]. The predominant DNA intrastrand crosslinks are removed by NER, the main DNA repair pathway dealing with lesions altering the helical structure of DNA, such as UV-induced
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
