Cisplatin Is a DNA-Damaging Antitumour Compound Triggering Multifactorial Biochemical Responses in Cancer Cells: Importance of Apoptotic Pathways

Yuliya      Sedletska; Marie-Josephe      Giraud-Panis; Jean-Marc      Malinge

doi:10.2174/1568011053765967

Abstract

cis-Diamminedichloroplatinum(II) (cisplatin) is among the most active antitumour agent used in human chemotherapy. The purpose of this review is to give an insight in several molecular mechanisms that mediate the sensitivity of cancer cells to this drug and to show how recent progress in our knowledge on some critical molecular events should lay the foundations of a more rational approach to anticancer drug design. Cisplatin is primarily considered as a DNA-damaging anticancer drug, mainly forming different types of bifunctional adducts in its reaction with cellular DNA. We will address the question of cellular activity disruption that cisplatin could cause through binding to more sensitive region of the genome such as telomeres. Cellular mechanisms of resistance to cisplatin are multifactorial and contribute to severe limitation in the use of this drug in clinics. They include molecular events modulating the amount of drug-DNA interaction, such as a reduction in cisplatin accumulation inside cancer cells or inactivation of cisplatin by thiol-containing species. Other important mechanisms acting downstream to the initial reaction of cisplatin with DNA, include an increase in adducts repair and a decrease in induction of apoptosis. Recently accumulating evidence suggest a role of the long patch DNA mismatch repair system in sensing cisplatin-damaged DNA and in triggering cell death through a c-Abl- and p73-dependent cascade; two other important pathways have been unravelled that are the mitogenactivated protein kinase cascade and the tumor suppressor p53. Several of these mechanisms underlying cisplatin resistance have been exploited to design new platinum derivatives. This issue will be covered in the present review.

Keywords: cisplatin, antitumour activity, drug resistance, apoptosis, dna mismatch repair, telomere

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