Cisplatin stops tubulin assembly into microtubules. A new insight into the mechanism of antitumor activity of platinum complexes.
Despite numerous studies considering DNA as a primary target of cisplatin attack, this work is the first to show the pure effect of cisplatin on the process of tubulin assembly/disassembly in vitro. When platinated, tubulin does not assemble into microtubules (direct electron microscopic studies). In place of them, highly stable and inert circled rings arise. Such tubulin aggregates are unable to participate in the process of chromosome separation during the mitosis, thus blocking cell division in living cells, which is a direct evidence of cisplatin antitumor activity. Cisplatin attack on tubulin causing blockage of tubulin assembly occurs via a two-step binding to GTP in the GTP center of tubulin ((195)Pt, (31)P NMR studies). The calculated binding rates are close to those reported in cisplatin-DNA interactions. The mechanism of cisplatin attack on tubulin is proposed.
Tulub
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Department of Biochemistry, Faculty of Biology of St. Petersburg State University, Universitetskaya Nab. 7/9, 199034, St. Petersburg, Russia.
Stefanov
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D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D017239:Paclitaxel / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry / Q000378:metabolism; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*
D000970:Antineoplastic Agents; D014404:Tubulin; D010984:Platinum; D006160:Guanosine Triphosphate; D017239:Paclitaxel; D002945:Cisplatin