Purpose The primary aim of this study was to determine cabazitaxel’s affinity for the ABCB1/P-glycoprotein (P-gp) trans- porter compared to first-generation taxanes. Methods We determined the kinetics of drug accumulation and retention using [ C]-labeled taxanes in multidrug-resistant (MDR) cells. In addition, membrane-enriched fractions isolated from doxorubicin-selected MES-SA/Dx5 cells were used to determine sodium orthovanadate-sensitive ATPase stimulation after exposure to taxanes. Custom [ H]-azido-taxane analogues were synthesized for the photoaffinity labeling of P-gp. Results The maximum intracellular drug concentration was achieved faster with [ C]-cabazitaxel (5 min) than [ C]-docetaxel (15–30 min). MDR cells accumulated twice as much cabazitaxel than docetaxel, and these levels could be restored to parental levels in the presence of the P-gp inhibitor PSC-833 (valspodar). Efflux in drug-free medium confirmed that MDR cells retained twice as much cabazitaxel than docetaxel. There was a strong association (r = 0.91) between the degree of taxane resistance conferred by P-gp expression and the accumulation differences observed with the two taxanes. One cell model expressing low levels of P-gp was not cross-resistant to cabazitaxel while demonstrating modest resistance to docetaxel. Furthermore, there was a 1.9 × reduction in sodium orthovanadate-sensitive ATPase stimulation resulting from treatment with cabazitaxel compared to docetaxel.
Cancer Chemotherapy and Pharmacology – Springer Journals
Published: Apr 19, 2018
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