Assessment of Critical DNA Damage Responsible for the Cytotoxicity of Anticancer Drugs

Anticancer drugs can concurrently generate three detrimental DNA lesions including DNA double-strand breaks (DSBs), DNA-protein cross-links (DPCs), and interstrand cross-links (ICLs) to varying degrees, and these lesions may differentially contribute to the toxicity of the drugs. However, no systematic studies have been performed about how much individual DSB, DPC, and ICL lesions contribute to cell killing upon treatment with anticancer drugs. Keeping this in mind, we treated HeLa cells with the equitoxic doses (LD20) of anticancer drugs and analyzed the induction of DSBs and DPCs. The association of ICLs with drug toxicity was assessed by the unique sensitivity of Chinese hamster ovary cells deficient in the xeroderma pigmentosum complementation group F gene. The results show that DNA lesions intimately associated with drug cytotoxicity vary significantly when HeLa cells are treated at the physiologically relevant doses. The critical cytotoxic DNA lesions are DSBsand DPCs for topoisomerase inhibitors (camptothecin and etoposide), DPCs for a DNA cytosine methyltransferase inhibitor (2’-deoxy -5-azacytidine), DPCs and ICLs for platinum drugs (cisplatin and oxaliplatin). Interestingly, cytotoxic DNA lesions are different for melphalan and mitomycin Calthough both are bifunctional alkylating agents. DSBs, DPCs, and ICLs are all associated with the cytotoxicity of melphalan, whereas ICLs alone are associated with the cytotoxicity of mitomycin C.Overall, our results provide a critical role of DPCs in anticancer drugs toxicity and raise the impact of DPC as a target for cancer therapies.

Author(s): Mahmoud I. Shoulkamy, Toshiaki Nakano, Xingzhi Xu and Hiroshi Ide

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