Inhibition of ABCB1 Expression Overcomes Acquired Docetaxel Resistance in Prostate Cancer

Abstract

Docetaxel is the first-line standard treatment for castration resistant prostate cancer (CRPC). However, relapse eventually occurs due to the development of resistance to docetaxel. In order to unravel the mechanism of acquired docetaxel resistance, we established docetaxel-resistant prostate cancer cells, TaxR, from castration resistant C4-2B prostate cancer cells. The IC50 for docetaxel in TaxR cells was about 70-fold higher than parental C4-2B cells. Global gene expression analysis revealed alteration of expression of a total of 1604 genes with 52% being upregulated and 48% downregulated. ABCB1, which belongs to the ATP-binding cassette (ABC) transporter family, was identified among the top upregulated genes in TaxR cells. The role of ABCB1 in the development of docetaxel resistance was examined. Knockdown of ABCB1 expression by its specific shRNA or inhibitor resensitized docetaxel resistant TaxR cells to docetaxel treatment by enhancing apoptotic cell death. Furthermore, we identified that apigenin, a natural product of the flavone family, inhibits ABCB1 expression and resensitizes docetaxel resistant prostate cancer cells to docetaxel treatment. Collectively, these results suggest that overexpression of ABCB1 mediates acquired docetaxel resistance and targeting ABCB1 expression could be potential approach to resensitize docetaxel resistant prostate cancer cells to docetaxel treatment.

Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer

“…ABCB1 transports a large number of hydrophobic compounds out of cells including cancer chemotherapeutics agents such as taxanes (like docetaxel,) anthracyclines, and alkaloids (33). We previously demonstrated that ABCB1 is overexpressed in docetaxel resistant TaxR cells compared to docetaxel sensitive C4-2B parental cells (23). Similarly, others have shown that ABCB1 is also overexpressed in docetaxel resistant DU145R and CWR22rv1R cells derived from parental DU145 and CWR22rv1 cells, respectively (34).…”

“…The cells were cultured in RPMI-1640 medium containing 10% complete fetal bovine serum (FBS) 100 units/mL penicillin and 0.1 mg/mL streptomycin and maintained at 37°C in a humidified incubator with 5% CO 2 . Docetaxel resistant C4-2B-TaxR (TaxR) and DU145-DTXR cells were generated from parental C4-2B and DU145 cells respectively by gradually increasing concentrations of docetaxel in the culture medium as previously described(23). TaxR and DU145-DTXR cells were maintained in 5 nM docetaxel-containing medium.…”

“…Our recent studies have also identified upregulation of ABCB1 as a common mechanism involved in acquired docetaxel resistance in CRPC(23). ABCB1 (P-glycoprotein, or MDR1) belongs to the ATP-binding cassette (ABC) transporters that use the energy produced during ATP hydrolysis to transport substrates, including taxanes such as docetaxel, across cell membranes and out of the cell.…”

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

“…ABCB1 belongs to the ATP-binding cassette transporters that use the energy of ATP hydrolysis to transport substrates across cell membranes, and ABCB1 overexpression results in diminished efficacy of anticancer drugs (30). Previous studies reported that increased ABCB1 conferred resistance to chemotherapeutic agents in several cancers (31)(32)(33). ABCB1 is also closely correlated with CSC-like properties and is one of the CSC markers (23).…”

Prognostic significance of ABCB1 in stage I lung adenocarcinoma

“…Thus, ABCB1 can affect the pharmacokinetics of administered drugs and the efficacy of chemotherapy agents for cancer. In fact, previous studies reported that increased ABCB1 expression conferred resistance to chemotherapeutic agents in several cancers (21,22). ABCB1 is closely associated with CSC-like properties and is considered one of the CSC-associated markers (6).…”