Cabazitaxel, a new taxane with favorable properties.

Cabazitaxel is a new taxane characterized by convenient administration, a favorable pharmacokinetic and safety profile and a decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance. In preclinical studies cabazitaxel inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp. Phase I clinical trials established that the cabazitaxel side effect profile is similar to that reported for taxanes, with neutropenia and neuropathy being the most commonly reported toxicities. Further clinical studies have revealed that cabazitaxel is clinically active in women with taxaneresistant metastatic breast cancer and in men with metastatic castration-resistant prostate cancer previously treated with docetaxel. The TROPIC phase III trial concluded that, compared to mitoxantrone/prednisone, the combination cabazitaxel/prednisone conferred a statistically significantly longer overall survival in patients after treatment with a docetaxel-containing regimen, providing the basis for its FDA approval in 2010.

Paclitaxel resistance in untransformed human mammary epithelial cells is associated with an aneuploidy-prone phenotype.

Despite its increasing clinical use, almost no data are currently available about paclitaxel effects on non-cancerous mammary epithelial cells. We have previously established paclitaxel-resistant sub-cell lines (paclitaxel-surviving populations, PSPs; n=20), and sensitive controls (control clones, CCs; n=10), from the untransformed human mammary epithelial cell line HME1. In this study, we aimed to establish whether paclitaxel resistance was associated with a modified sensitivity to paclitaxel-induced aneuploidy. For this purpose, we analysed basal and paclitaxel-induced chromosome missegregation, apoptosis and aberrant spindle multipolarisation as well as microtubular network composition for each subline. PSP sublines showed higher basal and paclitaxel-induced chromosome missegregation than the CC sublines. This phenomenon was associated with resistance to paclitaxel-induced apoptosis. No significant difference in paclitaxel-induced spindle pole abnormalities between CC and PSP sublines was found. Besides, we showed that a majority of PSPs display a constitutively disrupted microtubular network composition due to aberrant tubulin expression and post-translational modifications. These results clearly indicate that paclitaxel resistance in untransformed human mammary epithelial cells is related to an increased susceptibility to acquire aneuploidy in response to this agent. The consequences of these paclitaxel-associated alterations could be deleterious as they can potentially trigger tumorigenesis.