Transplatin is cytotoxic when photoactivated: enhanced formation of DNA cross-links

Pavla Heringova; Julie Woods; Fiona S. Mackay; Jana Kasparkova; Peter J. Sadler; Viktor Brabec

doi:10.1021/jm0606692

Transplatin is cytotoxic when photoactivated: enhanced formation of DNA cross-links

Pavla Heringova, Julie Woods, Fiona S. Mackay, Jana Kasparkova, Peter J. Sadler, Viktor Brabec

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Abstract

It is well-known that although cisplatin, [cis-[PtCl2(NH3)(2)], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm(-2)). Chemical studies show that light activates both chloride ligands of transplatin, and experiments on pSP73 plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark). Comet assays showed that UVA irradiation of transplatin-treated cells resulted in an increased inhibition of H2O2-induced DNA migration, supporting the conclusion that the cytotoxicity of photoactivated transplatin is mainly due to formation of DNA interstrand and DNA-protein cross-links.

Original language	English
Pages (from-to)	7792-7798
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	49
Issue number	26
DOIs	https://doi.org/10.1021/jm0606692
Publication status	Published - 2006

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title = "Transplatin is cytotoxic when photoactivated: enhanced formation of DNA cross-links",

abstract = "It is well-known that although cisplatin, [cis-[PtCl2(NH3)(2)], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm(-2)). Chemical studies show that light activates both chloride ligands of transplatin, and experiments on pSP73 plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark). Comet assays showed that UVA irradiation of transplatin-treated cells resulted in an increased inhibition of H2O2-induced DNA migration, supporting the conclusion that the cytotoxicity of photoactivated transplatin is mainly due to formation of DNA interstrand and DNA-protein cross-links.",

author = "Pavla Heringova and Julie Woods and Mackay, {Fiona S.} and Jana Kasparkova and Sadler, {Peter J.} and Viktor Brabec",

year = "2006",

doi = "10.1021/jm0606692",

language = "English",

volume = "49",

pages = "7792--7798",

journal = "Journal of Medicinal Chemistry",

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TY - JOUR

T1 - Transplatin is cytotoxic when photoactivated

T2 - enhanced formation of DNA cross-links

AU - Heringova, Pavla

AU - Woods, Julie

AU - Mackay, Fiona S.

AU - Kasparkova, Jana

AU - Sadler, Peter J.

AU - Brabec, Viktor

PY - 2006

Y1 - 2006

N2 - It is well-known that although cisplatin, [cis-[PtCl2(NH3)(2)], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm(-2)). Chemical studies show that light activates both chloride ligands of transplatin, and experiments on pSP73 plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark). Comet assays showed that UVA irradiation of transplatin-treated cells resulted in an increased inhibition of H2O2-induced DNA migration, supporting the conclusion that the cytotoxicity of photoactivated transplatin is mainly due to formation of DNA interstrand and DNA-protein cross-links.

AB - It is well-known that although cisplatin, [cis-[PtCl2(NH3)(2)], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm(-2)). Chemical studies show that light activates both chloride ligands of transplatin, and experiments on pSP73 plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark). Comet assays showed that UVA irradiation of transplatin-treated cells resulted in an increased inhibition of H2O2-induced DNA migration, supporting the conclusion that the cytotoxicity of photoactivated transplatin is mainly due to formation of DNA interstrand and DNA-protein cross-links.

U2 - 10.1021/jm0606692

DO - 10.1021/jm0606692

M3 - Article

C2 - 17181161

SN - 0022-2623

VL - 49

SP - 7792

EP - 7798

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 26

ER -

Transplatin is cytotoxic when photoactivated: enhanced formation of DNA cross-links

Abstract

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