Modulation of oxidative DNA damage and DNA-crosslink formation induced by cis-diammine-tetrachloro-platinum(IV) in the presence of endogenous reductants.
Platinum(IV) [Pt(IV)] complex, satraplatin, is currently in clinical trials for the treatment of various cancers. As a key step of the anti-cancer effect exertion, satraplatin is supposed to be reduced by endogenous reductants to platinum(II) [Pt(II)] complex. In this study, we investigated the interaction of DNA, Pt(IV), and the endogenous reductants such as ascorbic acid (AsA) and glutathione (GSH). As a model Pt(IV) compound, cis-diammine-tetrachloro-Pt(IV) [cis-Pt(IV)], which is a prodrug of cisplatin [cis-diammine-dichloro-Pt(II), cis-Pt(II)], was incubated with calf thymus DNA in the presence of AsA or GSH. In the presence of AsA, cis-Pt(IV) induced oxidative DNA damage. Hydroxyl radical scavengers suppressed the AsA-associated oxidative damage, thereby suggesting that hydroxyl radicals are involved in the DNA oxidation. cis-Pt(II)-like CD spectral change and crosslink formation in calf thymus DNA were also observed during this DNA oxidation, suggesting cis-Pt(IV) reduction by AsA and DNA conformational change induced by the newly formed cis-Pt(II) binding to DNA. GSH did not induce oxidative DNA damage likely due to its own hydroxyl radical scavenging ability. Further, GSH suppressed the Pt(II)-mediated DNA conformational change and crosslink formation, suggesting that GSH sequesters the cis-Pt(II) away from DNA by GSH-cis-Pt(II) complex formation.
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
Tsuyoshi
T
Nakai
Motozumi
M
Ando
Yoshinori
Y
Okamoto
Koji
K
Ueda
Nakao
N
Kojima
D001205:Ascorbic Acid / Q000737:chemistry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D004249:DNA Damage / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D005978:Glutathione / Q000737:chemistry; D008956:Models, Chemical; D009944:Organoplatinum Compounds / Q000737:chemistry*; D019163:Reducing Agents / Q000737:chemistry* / Q000494:pharmacology
D009944:Organoplatinum Compounds; D019163:Reducing Agents; C081294:satraplatin; D004247:DNA; C427203:calf thymus DNA; D005978:Glutathione; D001205:Ascorbic Acid