Tumour cells possess or acquire various mechanisms to circumvent the cytotoxic effects of
chemotherapy drugs. One such mechanism involves the overexpression of
ABC transporters that facilitate the extrusion of a variety of structurally distinct
chemotherapy drugs from the cytoplasm into the extracellular space. While specific
ABC transporter inhibitors have been developed, many affect other
ABC transporters, particularly at elevated concentrations. It is also unclear whether they show clear efficacy for combatting drug resistance in
cancer patients with minimal host toxicity. In this study, we demonstrate the ability of two
bile acids [β-
cholanic acid (
urso-
cholanic acid) and
deoxycholic acid] to specifically inhibit ABCC1-mediated
drug transport, augmenting
doxorubicin accumulation in breast and lung tumour cells selected for
doxorubicin resistance through overexpression of the ABCC1 (but not ABCB1)
drug transporter. The
bile acids could also restore uptake and sensitivity to
doxorubicin in human endothelial kidney cells genetically engineered to overexpress the ABCC1
drug transporter. These observations suggest a previously unreported role for
bile acids as ABCC1 inhibitors or regulators. Given its additional properties of minimal clinical toxicity in humans and its ability to inhibit
aldo-keto reductases involved in
anthracycline resistance and
anthracycline-induced
cardiotoxicity, β-
cholanic acid merits further in vivo and clinical investigation.