Azarenko Olga, Smiyun Gregoriy, Mah Jeffrey, Wilson Leslie, Jordan Mary Ann
Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California.
Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California
Mol Cancer Ther. 2014 Aug;13(8):2092-103. doi: 10.1158/1535-7163.MCT-14-0265. Epub 2014 Jun 30.
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.
卡巴他赛是一种新型化疗紫杉烷，对多西他赛耐药的细胞和肿瘤有效。它被批准用于治疗经多西他赛预处理的转移性激素难治性前列腺癌患者。在许多其他癌症中也观察到了客观反应，包括经预处理的转移性乳腺癌。卡巴他赛和多西他赛具有高度的结构相似性。卡巴他赛疗效的基础尚不清楚，其作用机制也未被描述。我们比较了卡巴他赛和多西他赛对表达荧光微管蛋白的MCF7人乳腺癌细胞的影响。两种药物均抑制细胞增殖（IC50，卡巴他赛为0.4±0.1 nmol/L，多西他赛为2.5±0.5 nmol/L），并通过诱导有丝分裂纺锤体异常使细胞停滞在中期。24小时时达到半数最大有丝分裂停滞所需的药物浓度相似（卡巴他赛为1.9 nmol/L，多西他赛为2.2 nmol/L）。卡巴他赛比多西他赛更有效地抑制微管动态不稳定性。特别是，卡巴他赛（2 nmol/L）使微管缩短率降低了59%（2 nmol/L多西他赛为49%），生长率降低了33%（多西他赛为19%），总体动态性降低了83%（多西他赛为64%）。卡巴他赛进入细胞的速度明显比多西他赛快，1小时内细胞内浓度达到25 μmol/L，而多西他赛则需要10小时。重要的是，洗涤后，细胞内卡巴他赛浓度仍然很高，而多西他赛浓度显著降低。数据表明，卡巴他赛在多西他赛耐药肿瘤中的效力归因于比多西他赛更强的微管动力学抑制、更快的药物摄取和更好的细胞内滞留。
