betaIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel.

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Smiyun G, Azarenko O, Miller H, Rifkind A, LaPointe NE, Wilson L, Jordan MA

betaIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel.

Cancer Chemother Pharmacol. 2017 Jul;80(1):151-164. doi: 10.1007/s00280-017-3345-2. Epub 2017 May 31.

PubMed ID

28567478 [ View in PubMed

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

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cabazitaxel	Tubulin beta-1 chain	Protein	Humans	Yes	Inhibitor	Details