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βIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel
Gregoriy Smiyun1, Olga Azarenko1, Herbert Miller1
1Department of Molecular, Cellular, and Developmental Biology, and the Neuroscience Research Institute, University of California Santa Barbara, Life Sciences Building, Room 1117, Santa Barbara, CA, 93106, USA.
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.
Insights
Cabazitaxel demonstrates superior efficacy against tumors overexpressing βIII-tubulin by potently stabilizing microtubules. This finding highlights cabazitaxel
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic hormone-refractory prostate cancer (mHSPC) treatment often involves taxanes like cabazitaxel and docetaxel.
- High βIII-tubulin isotype expression correlates with tumor aggressiveness and drug resistance.
- Understanding the molecular mechanisms behind cabazitaxel's efficacy is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the differential binding and microtubule-stabilizing effects of cabazitaxel and docetaxel in the presence and absence of βIII-tubulin.
- To determine if cabazitaxel's selective potency on βIII-tubulin-containing microtubules extends to its effects in human cancer cells.
- To elucidate the role of βIII-tubulin in mediating cabazitaxel's anti-tumor activity.
Main Methods:
- In vitro assembly of microtubules from purified bovine brain tubulin with or without βIII-tubulin.
- Assessment of radio-labeled cabazitaxel and docetaxel binding to microtubules.
- Measurement of microtubule dynamic instability (suppression of shortening rates, lengths, and dynamicity).
- In vitro studies using MCF7 human breast adenocarcinoma cells with normal and reduced βIII-tubulin levels (via siRNA knockdown).
- Evaluation of mitotic arrest induction in cancer cells.
Main Results:
- Cabazitaxel significantly suppressed microtubule dynamic instability more potently in the presence of βIII-tubulin compared to its absence.
- Docetaxel did not exhibit βIII-tubulin-enhanced microtubule stabilization.
- In MCF7 cells, cabazitaxel more effectively suppressed microtubule shortening and dynamicity, and induced mitotic arrest in cells with normal βIII-tubulin levels versus those with reduced levels.
- Docetaxel showed minimal βIII-tubulin-dependent effects on microtubule dynamics or mitotic arrest.
Conclusions:
- Cabazitaxel exhibits selective potency on microtubules containing βIII-tubulin in vitro and in cancer cells.
- The superior anti-tumor efficacy of cabazitaxel in tumors overexpressing βIII-tubulin may be attributed to its enhanced interaction with this specific tubulin isotype.
- Cabazitaxel represents a potentially unique microtubule-targeting agent for cancers characterized by high βIII-tubulin expression.
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