βIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel

Abstract

Cabazitaxel is a novel taxane approved for treatment of metastatic hormone-refractory prostate cancer in patients pretreated with docetaxel. Cabazitaxel, docetaxel, and paclitaxel bind specifically to tubulin in microtubules, disrupting functions essential to tumor growth. High levels of βIII-tubulin isotype expression are associated with tumor aggressivity and drug resistance. To understand cabazitaxel's increased efficacy, we examined binding of radio-labeled cabazitaxel and docetaxel to microtubules and the drugs' suppression of microtubule dynamic instability in vitro in microtubules assembled from purified bovine brain tubulin containing or devoid of βIII-tubulin. We found that cabazitaxel suppresses microtubule dynamic instability significantly more potently in the presence of βIII-tubulin than in its absence. In contrast, docetaxel showed no βIII-tubulin-enhanced microtubule stabilization. We also asked if the selective potency of cabazitaxel on βIII-tubulin-containing purified microtubules in vitro extends to cabazitaxel's effects in human tumor cells. Using MCF7 human breast adenocarcinoma cells, we found that cabazitaxel also suppressed microtubule shortening rates, shortening lengths, and dynamicity significantly more strongly in cells with normal levels of βIII-tubulin than after 50% reduction of βIII-tubulin expression by siRNA knockdown. Cabazitaxel also more strongly induced mitotic arrest in MCF7 cells with normal βIII-tubulin levels than after βIII-tubulin reduction. In contrast, docetaxel had little or no βIII-tubulin-dependent selective effect on microtubule dynamics or mitotic arrest. The selective potency of cabazitaxel on purified βIII-tubulin-containing microtubules and in cells expressing βIII-tubulin suggests that cabazitaxel may be unusual among microtubule-targeted drugs in its superior anti-tumor efficacy in tumors overexpressing βIII-tubulin.

Keywords: Cabazitaxel; Docetaxel; Microtubule; Taxane; Tubulin; βIII-tubulin.