title: Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype.
abstract: Eribulin mesylate (Halaven) is a microtubule-targeted anticancer drug used to treat patients with metastatic breast cancer who have previously received a taxane and an anthracycline. It binds at the plus ends of microtubules and has been shown to suppress plus end growth selectively. Because the class III β tubulin isotype is associated with resistance to microtubule targeting drugs, we sought to determine how βIII tubulin might mechanistically influence the effects of eribulin on microtubules. We found that while [(3)H]eribulin bound to bovine brain soluble tubulin depleted of βIII tubulin in a manner similar to that of unfractionated tubulin, it bound to plus ends of microtubules that were depleted of βIII-depleted tubulin with a maximal stoichiometry (20 ± 3 molecules per microtubule) higher than that of unfractionated microtubules (9 ± 2 molecules per microtubule). In addition, eribulin suppressed the dynamic instability behavior of βIII-depleted microtubules more strongly than and in a manner different from that of microtubules containing βIII tubulin. Specifically, with βIII tubulin present in the microtubules, 100 nM eribulin suppressed the growth rate by 32% and marginally reduced the catastrophe frequency (by 17%) but did not modulate the rescue frequency. However, in the absence of βIII tubulin, eribulin not only reduced the growth rate but also strongly reduced the shortening rate (by 43%) and the catastrophe and the rescue frequencies (by 49 and 32%, respectively). Thus, when present in microtubules, βIII tubulin substantially weakens the effects of eribulin.
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences , Mumbai, India.
authors.forename: Manu
authors.initials: M
authors.lastname: Lopus
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Herbert P
authors.initials: HP
authors.lastname: Miller
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Azarenko
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Riffle
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001923:Brain Chemistry; D002417:Cattle; D005663:Furans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007659:Ketones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008958:Models, Molecular; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D020033:Protein Isoforms; D014404:Tubulin; C490954:eribulin; D000095662:Polyether Polyketides