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

被引:29
作者
Bednarski, Patrick J. [1 ]
Korpis, Katharina [1 ]
Westendorf, Aron F. [1 ]
Perfahl, Steffi [1 ]
Gruenert, Renate [1 ]
机构
[1] Ernst Moritz Arndt Univ Greifswald, Dept Pharmaceut & Med Chem, Inst Pharm, D-17487 Greifswald, Germany
来源
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES | 2013年 / 371卷 / 1995期
关键词
apoptosis; autophagy; cancer; cisplatin; photoactivation; platinum diazides; ANTICANCER COMPLEX; VISIBLE-LIGHT; PLATINUM(IV); POTENT; DNA; PHOTOACTIVATION; ELIMINATION; APOPTOSIS; PATHWAYS; LINES;
D O I
10.1098/rsta.2012.0118
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Various Pt-IV 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 Pt-IV 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 Pt-IV diazides. Structures of some of the photolysis products were elucidated by LC-MS/MS; monoaqua-anddiaqua-Pt-II 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-Pt-II 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-Pt-IV 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.
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页数:15
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