Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1.
Cryptophycin 1 is a remarkably potent antiproliferative compound that shows excellent antitumor activity against mammary, colon, and pancreatic adenocarcinomas in mouse xenographs. At picomolar concentrations, cryptophycin 1 blocks cells in the G2/M phase of the cell cycle by an apparent action on microtubules. The compound binds to tubulin, inhibits microtubule polymerization, and depolymerizes preformed microtubules in vitro. Its exceptionally powerful antitumor activity (many-fold greater than paclitaxel or the vinca alkaloids) raises important questions about its mechanism of action. By quantitative video microscopy, we examined the effects of cryptophycin 1 on the dynamics of individual microtubules assembled to steady state from bovine brain tubulin. At low nanomolar concentrations, in the absence of net microtubule depolymerization, cryptophycin 1 potently stabilized microtubule dynamics. It reduced the rate and extent of microtubule shortening and growing and increased the frequency of rescue. The results suggest that cryptophycin 1 exerts its antiproliferative and antimitotic activity by binding reversibly and with high affinity to the ends of microtubules, perhaps in the form of a tubulin-cryptophycin 1 complex, resulting in the most potent suppression of microtubule dynamics yet described.
Panda
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Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
Himes
R H
RH
Moore
R E
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Wilson
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Jordan
M A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001921:Brain; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D047630:Depsipeptides; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D018715:Microscopy, Video; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000187:drug effects* / Q000302:isolation & purification; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D014404:Tubulin; C088419:cryptophycin