title: Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype.
abstract: Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration. They continually undergo dynamic instability, periods of slow growth and rapid shortening that are crucial to these cell functions. We determined ixabepilone's microtubule binding and polymerization effects in vitro and also determined its effects on inhibition of dynamic instability in vitro and in cells, both with and without removal of the βIII isotype of tubulin. The βIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of βIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone. Depletion of βIII-tubulin from MCF7 human breast cancer cells also induced increased mitotic arrest by ixabepilone. Thus, βIII-tubulin expression suppresses the antitumor effects of ixabepilone, indicating that increased βIII-tubulin may be an important contributor to the development of resistance to ixabepilone.
authors.affiliation: Department of Molecular, Cellular, and Development Biology, University of California Santa Barbara, Santa Barbara, CA, 93105, USA.|Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, Kalina, Santacruz East, Mumbai, 400098, India.
authors.forename: Manu
authors.initials: M
authors.lastname: Lopus
authors.affiliation: Department of Molecular, Cellular, and Development Biology, University of California Santa Barbara, Santa Barbara, CA, 93105, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Smiyun
authors.affiliation: Department of Molecular, Cellular, and Development Biology, University of California Santa Barbara, Santa Barbara, CA, 93105, USA.
authors.forename: Herb
authors.initials: H
authors.lastname: Miller
authors.affiliation: Department of Molecular, Cellular, and Development Biology, University of California Santa Barbara, Santa Barbara, CA, 93105, USA.|Dako Agilent Technologies, 6392 Via Real, Carpinteria, CA, 93013, USA.
authors.forename: Emin
authors.initials: E
authors.lastname: Oroudjev
authors.affiliation: Department of Molecular, Cellular, and Development Biology, University of California Santa Barbara, Santa Barbara, CA, 93105, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Department of Molecular, Cellular, and Development Biology, University of California Santa Barbara, Santa Barbara, CA, 93105, USA. jordan@lifesci.ucsb.edu.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001923:Brain Chemistry; D001943:Breast Neoplasms / Q000473:pathology; D002417:Cattle; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C498585:TUBB3 protein, human; D014404:Tubulin; D050257:Tubulin Modulators; C430592:ixabepilone; D017239:Paclitaxel
keywords: Breast cancer; Epothilone; Ixabepilone; Microtubule; Tubulin; βIII-tubulin