PURPOSE: Hemiasterlin, hemiasterlin A and hemiasterlin B are newly isolated cytotoxic tripeptides with potential as antitumor drugs. We wished to determine their mechanism of cytotoxicity. METHODS: We studied their effect on cell survival, cell cycle progression, and microtubule morphology in MCF-7 human mammary carcinoma cells. RESULTS: At the nanomolar concentrations at which they were cytotoxic, the peptides induced arrest in mitotic metaphase. Hemiasterlin A produced abnormal mitotic spindles like those produced by the microtubule inhibitors taxol, nocodazole and vinblastine at low concentrations. At high concentrations hemiasterlin A did not cause microtubule bundling like taxol, but caused microtubule depolymerization like nocodazole and vinblastine. CONCLUSIONS: The hemiasterlins probably exert their cytotoxic effect by inhibiting spindle microtubule dynamics.
PURPOSE:Hemiasterlin, hemiasterlin A and hemiasterlin B are newly isolated cytotoxictripeptides with potential as antitumor drugs. We wished to determine their mechanism of cytotoxicity. METHODS: We studied their effect on cell survival, cell cycle progression, and microtubule morphology in MCF-7 human mammary carcinoma cells. RESULTS: At the nanomolar concentrations at which they were cytotoxic, the peptides induced arrest in mitotic metaphase. Hemiasterlin A produced abnormal mitotic spindles like those produced by the microtubule inhibitors taxol, nocodazole and vinblastine at low concentrations. At high concentrations hemiasterlin A did not cause microtubule bundling like taxol, but caused microtubule depolymerization like nocodazole and vinblastine. CONCLUSIONS: The hemiasterlins probably exert their cytotoxic effect by inhibiting spindle microtubule dynamics.
Authors: Reza Rezaei Darestani; Philip Winter; Elena N Kitova; Jack A Tuszynski; John S Klassen Journal: J Am Soc Mass Spectrom Date: 2016-03-04 Impact factor: 3.109