Effects of light-activated diazido-PtIV complexes on cancer cells in vitro

Abstract

Various PtIV diazides have been investigated over the years as light-activatable prodrugs that interfere with cell proliferation, accumulate in cancer cells and cause cell death. The potencies of the complexes vary depending on the substituted amines (pyridine= piperidine ammine) as well as the coordination geometry (trans diazide>cis). Light-activated PtIV diazides tend to be less specific than cisplatin at inhibiting cancer cell growth, but cells resistant to cisplatin show little cross-resistance to PtIV diazides. Platinum is accumulated in the cancer cells to a similar level as cisplatin, but only when activated by light, indicating that reactive Pt species form photolytically. Studies show that Pt also becomes attached to cellular DNA upon the light activation of various PtIV diazides. Structures of some of the photolysis products were elucidated by LC-MS/MS; monoaqua- and diaqua-PtII complexes form that are reactive towards biomolecules such as calf thymus DNA. Platination of calf thymus DNA can be blocked by the addition of nucleophiles such as glutathione and chloride, further evidence that aqua-PtII species form upon irradiation. Evidence is presented that reactive oxygen species may be generated in the first hours following photoactivation. Cell death does not take the usual apoptotic pathways seen with cisplatin, but appears to involve autophagy. Thus, photoactivated diazido-PtIV complexes represent an interesting class of potential anti-cancer agents that can be selectively activated by light and kill cells by a mechanism different to the anti-cancer drug cisplatin. © 2013 The Author(s) Published by the Royal Society. All rights reserved.