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Mechanism of Action of the Microtubule-Targeted Antimitotic Depsipeptide Tasidotin (Formerly ILX651) and Its Major Metabolite Tasidotin C-Carboxylate

¹ Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California, Santa Barbara, California; ² Genzyme Corp., San Antonio, Texas; and ³ Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas

Requests for reprints: Leslie Wilson, Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106-9610. Phone: 805-893-2819; Fax: 805-893-8094; E-mail: Wilson{at}lifesci.ucsb.edu.

Tasidotin (ILX-651), an orally active synthetic microtubule-targeted derivative of the marine depsipeptide dolastatin-15, is currently undergoing clinical evaluation for cancer treatment. Tasidotin inhibited proliferation of MCF7/GFP breast cancer cells with an IC₅₀ of 63 nmol/L and inhibited mitosis with an IC₅₀ of 72 nmol/L in the absence of detectable effects on spindle microtubule polymer mass. Tasidotin inhibited the polymerization of purified tubulin into microtubules weakly (IC₅₀ 30 µmol/L). However, it strongly suppressed the dynamic instability behavior of the microtubules at their plus ends at concentrations 5 to 10 times below those required to inhibit polymerization. Its major actions were to reduce the shortening rate, the switching frequency from growth to shortening (catastrophe frequency), and the fraction of time the microtubules grew. In contrast with all other microtubule-targeted drugs thus far examined that can inhibit polymerization, tasidotin did not inhibit the growth rate. In contrast to stabilizing plus ends, tasidotin enhanced microtubule dynamic instability at minus ends, increasing the shortening length, the fraction of time the microtubules shortened, and the catastrophe frequency and reducing the rescue frequency. Tasidotin C-carboxylate, the major intracellular metabolite of tasidotin, altered dynamic instability of purified microtubules in a qualitatively similar manner to tasidotin but was 10 to 30 times more potent. The results suggest that the principal mechanism by which tasidotin inhibits cell proliferation is by suppressing spindle microtubule dynamics. Tasidotin may be a relatively weak prodrug for the functionally active tasidotin C-carboxylate. [Cancer Res 2007;67(8):3767–76]

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