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: Leslie Wilson, Manu Lopus, Herbert P Miller, Olga Azarenko, Stephen Riffle, Jennifer A Smith, Mary Ann Jordan
• Journal: Biochemistry (Biochemistry) Vol. 54 Issue 42 Pg. 6482-9 (Oct 27 2015) ISSN: 1520-4995 [Electronic] United States
• PMID: 26435331 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Furans
• Ketones
• Protein Isoforms
• Tubulin
• eribulin

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology)
• Binding Sites
• Brain Chemistry
• Cattle
• Furans (adverse effects, pharmacokinetics, pharmacology)
• Humans
• In Vitro Techniques
• Ketones (adverse effects, pharmacokinetics, pharmacology)
• Microtubules (chemistry, drug effects, metabolism)
• Models, Molecular
• Peripheral Nervous System Diseases (chemically induced)
• Protein Binding
• Protein Isoforms (chemistry, metabolism)
• Tubulin (chemistry, metabolism)