Antiproliferative Mechanism of Action of the Novel Taxane Cabazitaxel as Compared with the Parent Compound Docetaxel in MCF7 Breast Cancer Cells

Abstract

Cabazitaxel, a novel chemotherapeutic taxane, is effective against docetaxel-resistant cells and tumors. It is approved for treatment of metastatic hormone-refractory prostate cancer in patients pretreated with docetaxel. Objective responses have been observed in many other cancers, including pretreated metastatic breast cancer. Cabazitaxel and docetaxel share a high degree of structural similarity. The basis for cabazitaxel's efficacy is unclear, and its mechanism has not been described. We compared the effects of cabazitaxel and docetaxel on MCF7 human breast cancer cells expressing fluorescent tubulin. Both drugs inhibited cell proliferation (IC 50s , cabazitaxel, 0.4 AE 0.1 nmol/L, docetaxel, 2.5 AE 0.5 nmol/L) and arrested cells in metaphase by inducing mitotic spindle abnormalities. Drug concentrations required for halfmaximal mitotic arrest at 24 hours were similar (1.9 nmol/L cabazitaxel and 2.2 nmol/L docetaxel). Cabazitaxel suppressed microtubule dynamic instability significantly more potently than docetaxel. In particular, cabazitaxel (2 nmol/L) suppressed the microtubule shortening rate by 59% (compared with 49% for 2 nmol/L docetaxel), the growing rate by 33% (vs. 19%), and overall dynamicity by 83% (vs. 64%). Cabazitaxel was taken up into cells significantly faster than docetaxel, attaining an intracellular concentration of 25 mmol/L within 1 hour, compared with 10 hours for docetaxel. Importantly, after washing, the intracellular cabazitaxel concentration remained high, whereas the docetaxel concentration was significantly reduced. The data indicate that the potency of cabazitaxel in docetaxel-resistant tumors is due to stronger suppression of microtubule dynamics, faster drug uptake, and better intracellular retention than occurs with docetaxel.

Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer

“…These observations indicate that cabazitaxel is less dependent on its inhibitory effects on the AR pathway, and exerts greater antitumor activity via AR-independent mechanisms compared to docetaxel. This is concordant with clinical observations [7,8], and is probably caused by a higher potency of cabazitaxel in suppressing microtubule dynamics compared to docetaxel, with faster drug uptake and better intracellular retention [10]. This is further supported by the lower Ki67 expression observed in our enzalutamide-resistant tumors treated with cabazitaxel compared to docetaxel, indicating stronger antiproliferative properties.…”

Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer

“…Cabazitaxel can effectively stabilize microtubule structures in androgen-sensitive and CRPC cells in accordance with the known action of this taxane chemotherapeutic agent (14,45). With the knowledge that Cabazitaxel was designed to bind with β-tubulin subunits and stabilize their interaction preventing depolymerization of the structure, once assembled, the microtubules cannot disassemble leading to mitotic blockade.…”

Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype

“…Shortly after purchase (ATCC, 2007), cells were transfected with enhanced green fluorescent protein EGFP-α-tubulin vector (Clontech Laboratories) as described in detail in [23]. The EGFP-α-tubulin-expressing MCF7 cells were indistinguishable from unmodified MCF7 cells except for their fluorescent microtubules and their doubling time of 35 h, which was 20 % slower than that of unmodified MCF7 cells.…”