Molecular basis of resistance to the microtubule-depolymerizing antitumor compound plocabulin.

ABSTRACT: Plocabulin (PM060184) is a microtubule depolymerizing agent with potent antiproliferative activity undergoing phase II clinical trials for the treatment of solid tumors. Plocabulin shows antifungal activity virtually abolishing growth of the filamentous fungus Aspergillus nidulans. A. nidulans hyphae depend both on mitotic and interphase microtubules, as human cells. Here, we exploited the A. nidulans genetic amenability to gain insight into the mechanism of action of plocabulin. By combining mutations in the two A. nidulans β-tubulin isotypes we obtained a plocabulin-insensitive strain, showing that β-tubulin is the only molecular target of plocabulin in fungal cells. From a genetic screen, we recovered five mutants that show plocabulin resistance but do not carry mutations in β-tubulin.

SUBMITTER: Pantazopoulou A 

PROVIDER: S-EPMC5988728 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature