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Chem Biol. 2003 Jul;10(7):597-607.

Microtubule alterations and mutations induced by desoxyepothilone B: implications for drug-target interactions.

Author information

1
Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, 2031, Australia.

Abstract

Epothilones, like paclitaxel, bind to beta-tubulin and stabilize microtubules. We selected a series of four leukemia sublines that display increasing levels of resistance to the epothilone analog desoxyepothilone B (dEpoB). The dEpoB cells selected in 30-140 nM were approximately 15-fold cross-resistant to paclitaxel, while 300 nM selected cells were 467-fold resistant to this agent. The dEpoB-selected cells are hypersensitive to microtubule destabilizing agents, and express increased levels of class III beta-tubulin and MAP4. A novel class I beta-tubulin mutation, A231T, that affects microtubule stability but does not alter paclitaxel binding, was identified. The 300 nM selected cells acquired a second mutation, Q292E, situated near the M loop of class I beta-tubulin. These cells fail to undergo drug-induced tubulin polymerization due to dramatically reduced drug binding. The dEpoB-resistant leukemia cells provide novel insights into microtubule dynamics and, in particular, drug-target interactions.

PMID:
12890533
DOI:
10.1016/s1074-5521(03)00141-8
[Indexed for MEDLINE]

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