$\beta$III-tubulin enhances efficacy of cabazitaxel as compared with docetaxel

Title$\beta$III-tubulin enhances efficacy of cabazitaxel as compared with docetaxel
Publication TypeJournal Article
Year of Publication2017
AuthorsSmiyun G, Azarenko O, Miller H, Rifkind A, LaPointe NE, Wilson L, Jordan MAnn
JournalCancer Chemotherapy and Pharmacology

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 $\beta$III-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 $\beta$III-tubulin. We found that cabazitaxel suppresses microtubule dynamic instability significantly more potently in the presence of $\beta$III-tubulin than in its absence. In contrast, docetaxel showed no $\beta$III-tubulin-enhanced microtubule stabilization. We also asked if the selective potency of cabazitaxel on $\beta$III-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 $\beta$III-tubulin than after 50{%} reduction of $\beta$III-tubulin expression by siRNA knockdown. Cabazitaxel also more strongly induced mitotic arrest in MCF7 cells with normal $\beta$III-tubulin levels than after $\beta$III-tubulin reduction. In contrast, docetaxel had little or no $\beta$III-tubulin-dependent selective effect on microtubule dynamics or mitotic arrest. The selective potency of cabazitaxel on purified $\beta$III-tubulin-containing microtubules and in cells expressing $\beta$III-tubulin suggests that cabazitaxel may be unusual among microtubule-targeted drugs in its superior anti-tumor efficacy in tumors overexpressing $\beta$III-tubulin.