Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

Publikace: CHEMICAL RESEARCH IN TOXICOLOGY 25, 1099-1111 Autoři: Pracharova, J., Zerzankova, L., Stepankova, J., Novakova, O., Farrer, NJ., Sadler, PJ., Brabec, V., Kasparkova, J. Rok: 2012

Abstrakt

The Pt-IV diazido complex trans,trans,trans-[Pt-(N-3)(2)(OH)(2)(pyridine)(2)] (1) is unreactive in the dark but is cytotoxic when photoactivated by UVA and visible light. We have shown that 1 when photoactivated accumulates in tumor cells and binds strongly to nuclear DNA under conditions in which it is toxic to tumor cells. The nature of the DNA adducts, including conformational alterations, induced by photoactivated 1 are distinctly different from those produced in DNA by conventional cisplatin or transplatin. In addition, the observation that major DNA adducts of photoactivated 1 are able to efficiently stall RNA polymerase II more efficiently than cisplatin suggests that transcription inhibition may contribute to the c-ytotoxicity levels observed for photoactivated 1. Hence, DNA adducts of 1 could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. The findings of the present work help to explain the different cytotoxic effects of photoactivated 1 and conventional cisplatin and thereby provide new insights into mechanisms associated with the antitumor effects of platinum complexes photoactivated by UVA and visible light.