The role of bile acids in overcoming resistance to chemotherapy

Abstract

In the context of cancer therapy, resistance to chemotherapy agents is a serious threat to patient welfare. In these circumstances, patients can either present with cancers that are naturally resistant to conventional therapy, referred to as innate resistance, or with cancers that become resistant following treatment, referred to as acquired resistance. In this thesis, we address the phenomenon of acquired drug resistance, involving cell lines selected for resistance to the anthracycline, doxorubicin. In the first study, we examined the role of the aldo-keto reductases AKR1C3 and AKR1B10 in doxorubicin resistance, enzymes that can hydroxylate doxorubicin to a less toxic form (doxorubicinol). Additionally, these enzymes can function to promote estrogen biosynthesis from estrone, which can have significant effects on cell growth and survival. We demonstrated in the first study that AKR1C3 and AKR1B10 are expressed at higher levels in doxorubicin resistant MCF-7 cells than their isogenic control counterparts. This change in expression correlated very well with increased estrogen synthesis. siRNA-mediated reduction in AKR1C3 and/or AKR1B10 transcript expression had no major effect on doxorubicin resistance, suggesting that these enzymes are not sufficient to mediate the doxorubicin resistance phenotype and that other mechanisms of doxorubicin resistance exist in these cells. We did, however, note that a pharmacological inhibitor of AKR enzymes (a bile acid termed β-cholanic acid) was effective in reversing doxorubicin resistance in doxorubicin-selected cell lines. This prompted a second study to investigate the mechanism for this reversal. We observed that β-cholanic acid strongly reduced doxorubicin resistance in cell lines that express the ABC transporter ABCC1, including doxorubicin-resistant MCF-7 breast tumour cells and H-69 lung cancer cells. Reversal of doxorubicin resistance was also observed in HEK293 cells transfected with ABCC1 expression vectors. Subsequent experiments confirmed that β-cholanic acid and another bile acid that does not inhibit the aldo-keto reductases was able to inhibit ABCC1-mediate doxorubicin efflux from tumour cells, thereby providing a mechanism for the reversal of doxorubicin resistance. Bile acids thus represent an important new class of compounds that could prove useful in improving the effectiveness of doxorubicin chemotherapy in cancer patients, specifically in recurrent tumours overexpressing the ABCC1 transporter.