Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

Abstract

The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, antihypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite 7-ethyl-10-hydroxycamptothecin, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic, and ovarian cancers, suggesting potential roles for OATPs in tumor development and progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.

Fig. 1.

Organ-specific expression of drug transporters. The expression of transporters at the apical and basolateral membranes of various tissues plays a crucial role in the transport of both endogenous and exogenous substrates across membranes. In the liver and kidney, transporters mediate movement of substrates into hepatocytes or the proximal tubule cells, respectively, where the substrates may undergo biotransformation or be excreted unmodified into the bile or urine via other transporters. In the intestine, transporters are involved in the selective movement of substrates into and out of enterocytes, which affects the oral bioavailability of drugs. In the capillary endothelial cells of the blood-brain barrier, transporters control which substrates can cross from the bloodstream into brain cells, thus limiting the ability of certain substrates to penetrate brain tissue. For the liver, the bloodstream compartment refers to the portal venous circulation. ASBT, apical sodium-dependent bile acid transporter; BCRP, breast cancer resistance protein; ENT, equilibrative nucleoside transporter; MATE, multidrug and toxic compound extrusion; MCT, monocarboxylate transporter; MRP, multidrug resistance-associated protein; NTCP, sodium/taurocholate cotransporting polypeptide; OAT, organic anion transporter; OST, organic solute and steroid transporter; PEPT, peptide transporter; P-gp, P-glycoprotein.