title: 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 (IC50s, cabazitaxel, 0.4 ± 0.1 nmol/L, docetaxel, 2.5 ± 0.5 nmol/L) and arrested cells in metaphase by inducing mitotic spindle abnormalities. Drug concentrations required for half-maximal 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 μmol/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.
authors: Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California.
authors: Olga
authors: O
authors: Azarenko
authors: Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California.
authors: Gregoriy
authors: G
authors: Smiyun
authors: Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California.
authors: Jeffrey
authors: J
authors: Mah
authors: Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California.
authors: Leslie
authors: L
authors: Wilson
authors: Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California jordan@lifesci.ucsb.edu.
authors: Mary Ann
authors: MA
authors: Jordan
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation / Q000187:drug effects*; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D055550:Protein Stability; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel; C552428:cabazitaxel