Potentiation of cytotoxic action of cis-[PtCl2(NH3)(1M7AI)] by UVA irradiation. Mechanistic insights

The design of photosensitive platinum antitumor drugs has been shown to be a very promising approach to enhance the low selectivity of antitumor platinum drugs towards cancer tissues. Here, we show that UVA irradiation can substantially potentiate the toxicity of a cisplatin derivative, cis-[PtCl2(NH3)(1-methyl-7-azaindole)], in tumor cells. We used methods of molecular biophysics and cellular biology to investigate the mechanism underlying this effect. We find that the enhanced phototoxicity of cis-[PtCl2(NH3)(1-methyl-7-azaindole)] is connected with the capability of this complex to cleave DNA strands. We demonstrate that production of reactive singlet oxygen, conditioned by the presence of the 1-methyl-7-azaindole ligand, is responsible for the cleavage of DNA strands not only in vitro but also in living cells. Our findings also reveal that UVA irradiation of DNA modified by cis-[PtCl2(NH3)(1-methyl-7-azaindole)] may result in a significant increase in the number of more toxic interstrand cross-links in DNA. Collectively, these data provide convincing evidence that the replacement of the ammine in the molecule of cisplatin by the 1-methyl-7-azaindole ligand might lead to a new potential candidate for photoactivated chemotherapy (PACT) against some types of cancer.