ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) are not primary resistance factors for cabazitaxel

Abstract

Introduction: ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells. Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette (ABC) transporters.

Methods: We determined the effects of cabazitaxel, a novel tubulin-binding taxane, and paclitaxel on paclitaxel-resistant, ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant, ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.

Results: Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2, LLC-MDR1-WT, and HEK293/ABCC10 cells. Moreover, cabazitaxel had low efficacy, whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1, indicating a direct interaction of both drugs with the transporter.

Conclusion: ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel, suggesting that cabazitaxel may have a low affinity for these efflux transporters.

Figure 1

Cytotoxicity of paclitaxel and cabazitaxel in ABCB1- and ABCC10-overexpressing cells. ABCB1, ATP-binding cassette subfamily B member 1; ABCC10, ATP-binding cassette subfamily C member 10. The cytotoxicity of paclitaxel and cabazitaxel was determined by the MTT assay in ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells, ABCC10-overexpressing HEK293/ABCC10 cells, and their parental KB-3-1, LLC-PK1, and HEK293/pcDNA3.1 cells. Error bars indicate the standard deviation (SD). Significantly elevated resistance of KB-C2 (A) and LLC-MDR1-WT cells (C) to paclitaxel, none or low-level resistance of KB-C2 (B) and LLC-MDR1-WT cells (D) to cabazitaxel, significantly elevated resistance of HEK293/ABCC10 cells to paclitaxel (E), and no resistance of HEK293/ABCC10 cells to cabazitaxel (F) are observed as compared with those of their parental cells.

Figure 2

Stimulation of ABCB1 ATPase activity by paclitaxel and cabazitaxel. Vanadate-sensitive ABCB1 ATPase activity was stimulated in the presence of the indicated concentrations of paclitaxel and cabazitaxel. Error bars indicate the SD.