Cabazitaxel is more active than first-generation taxanes in ABCB1(+) cell lines due to its reduced affinity for P-glycoprotein

Autor: Diego A. Gianolio, Volker Derdau, Nicolas Philippe, George E. Duran, Jens Atzrodt, Dietmar Weitz, Jörg Blankenstein, Dorothée Semiond, Sandrine Mace, Branimir I. Sikic
Rok vydání: 2018
Předmět:
Zdroj: Cancer Chemotherapy and Pharmacology. 81:1095-1103
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-018-3572-1
Popis: The primary aim of this study was to determine cabazitaxel’s affinity for the ABCB1/P-glycoprotein (P-gp) transporter compared to first-generation taxanes. We determined the kinetics of drug accumulation and retention using [14C]-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 [3H]-azido-taxane analogues were synthesized for the photoaffinity labeling of P-gp. The maximum intracellular drug concentration was achieved faster with [14C]-cabazitaxel (5 min) than [14C]-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 (r2 = 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. We calculated a dissociation constant (Kd) value of 1.7 µM for [3H]-azido-docetaxel and ~ 7.5 µM for [3H]-azido-cabazitaxel resulting in a 4.4 × difference in P-gp labeling, and cold docetaxel was a more effective competitor than cabazitaxel. Our studies confirm that cabazitaxel is more active in ABCB1(+) cell models due to its reduced affinity for P-gp compared to docetaxel.
Databáze: OpenAIRE
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