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. 2010 Aug 8:2010:201367.
doi: 10.4061/2010/201367.

Cellular responses to Cisplatin-induced DNA damage

Alakananda Basu  1 , Soumya Krishnamurthy
Affiliations

Cellular responses to Cisplatin-induced DNA damage

Alakananda Basu et al. J Nucleic Acids. .

Abstract

Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

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Figures

Figure 1
Figure 1
Cellular responses to cisplatin-induced DNA damage. [1] Entry of cisplatin into cells by passive diffusion (indicated by dotted arrows), carrier-mediated transport, employing copper transporter-1 (CTR1). [2] Efflux of cisplatin from the cells by the ATP-dependent transporters, ATP7A and ATP7B. [3] Cisplatin binds to cellular thiols, such as glutathione and metallothionein. The glutathione-cisplatin conjugates are further transported from the cells by the ATP-dependent, GS-X pumps. [4] Once cisplatin interacts with DNA, it stalls cell proliferation by inhibiting DNA synthesis, followed by activation of DNA damage response. [5] Cisplatin-DNA adducts is primarily repaired via the nucleotide excision repair (NER) system and also induces cell-cycle arrest. The DNA damage response is transduced mainly via p53 and c-Abl. Cisplatin-induced DNA damage activates p53, leading to the induction of p21, GADD45, proapoptotic PUMAα, caspase-6, -7, and microRNAs such as miR-34a. p53 also promotes cisplatin-induced apoptosis by binding and inhibiting the antiapoptotic Bcl-xL and also by degradation of FLIP. Cisplatin-DNA adducts activates the mismatch repair system which further activates c-Abl, leading to the activation of JNK and p38 MAPK and stabilization of p73 resulting in apoptosis. [6] Kinases such as PKC, ERK, and Akt are also involved in the regulation of cisplatin-induced cell death. [7] miR-214 promotes cisplatin resistance by downregulating PTEN and activating Akt.
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