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Tumor Cells Resistant to a Microtubule-Depolymerizing Hemiasterlin Analogue, HTI-286, Have Mutations in α- or β-Tubulin and Increased Microtubule Stability

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Cancer Therapeutics Branch, The NCI Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, Molecular and Cell Biology Department, Howard Hughes Medical Institute, University of California, Berkeley, California 94720, Oncology Research, Wyeth Research, Pearl River, New York 10965, and National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892
Cite this: Biochemistry 2004, 43, 44, 13944–13954
Publication Date (Web):October 15, 2004
https://doi.org/10.1021/bi049300+
Copyright © 2004 American Chemical Society

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    Abstract

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    Hemiasterlins are sponge-derived tripeptides that inhibit cell growth by depolymerizing existing microtubules and inhibiting microtubule assembly. Since hemiasterlins are poor substrates for P-glycoprotein, they are attractive candidates for cancer therapy and have been undergoing clinical trials. The basis of resistance to a synthetic analogue of hemiasterlin, HTI-286 (HTI), was examined in cell populations derived from ovarian carcinoma (A2780/1A9) cells selected in HTI-286. 1A9-HTI-resistant cells (1A9-HTIR series) were 57−89-fold resistant to HTI. Cross-resistance (3−186-fold) was observed to other tubulin depolymerizing drugs, with collateral sensitivity (2−14-fold) to tubulin polymerizing agents. Evaluation of the percentage of polymerized and soluble tubulin in 1A9 parental and 1A9-HTIR cells corroborated the HTI cytotoxicity data. At 22 °C or 37 °C, in the absence of any drug, the percentage of polymerized microtubules for each of the 1A9-HTIR populations was greater than that in the 1A9 parental cells, consistent with more stable microtubules. Furthermore, microtubules in the 1A9-HTIR populations were also more resistant to depolymerization at 4 °C and had more acetylated and detyrosinated (Glu-tubulin) α-tubulin, all characteristic of more stable microtubules. The 1A9-HTIR cell populations exhibited either a single nucleotide change in the M40 β-tubulin isotype, S172A, or in two cell populations where no β-tubulin mutation was detected, mutations in the Kα-1 α-tubulin isotype, S165P and R221H in one resistant cell population and I384V in another. Unlike reports of mutations resulting in reduced drug affinity, the experimental data and location of mutations are consistent with resistance to HTI-286 mediated by microtubule-stabilizing mutations in β- or α-tubulin.

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    *

     Corresponding author. Telephone:  (301) 496-6611. Fax:  (301) 402-1608. E-mail:  [email protected].

     National Cancer Institute.

    §

     Present address:  University of Ulasan, Asan Medical Center, Department of Obstetrics & Gynecology, Seoul, Korea.

     University of California.

     Wyeth Research.

    #

     National Institutes of Health.

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