Organic anion-transporting polypeptide 2B1 (OATP2B1) is a multispecific transporter mediating the cellular
uptake of steroids and numerous drugs. OATP2B1 is abundantly expressed in the intestine and is also present in
various tumors. Increased steroid hormone uptake by OATP2B1 has been suggested to promote progression of
hormone dependent tumors. 13α-estrones are effective inhibitors of endogenous estrogen formation and are
potential candidates to inhibit proliferation of hormone dependent cancers. Recently, we have identified a variety
of 13α/β-estrone-based inhibitors of OATP2B1. However, the nature of this interaction, whether these
inhibitors are potential transported substrates of OATP2B1 and hence may be enriched in OATP2B1-
overexpressing cells, has not yet been investigated. In the current study we explored the antiproliferative effect
of the most effective OATP2B1 inhibitor 13α/β-estrones in control and OATP2B1-overexpressing A431
carcinoma cells. We found an increased antiproliferative effect of 3-O-benzyl 13α/β-estrones in both mock
transfected and OATP2B1-overexpressing cells. However, C-2 halogenated 13α-estrones had a selective
OATP2B1-mediated cell growth inhibitory effect. In order to demonstrate that increased sensitization can be
attributed to OATP2B1-mediated cellular uptake, tritium labeled 2-bromo-13α-estrone was synthesized for direct
transport measurements. These experiments revealed increased accumulation of [3H]2-bromo-13α-estrone due to
OATP2B1 function. Our results indicate that C-2 halogenated 13α-estrones are good candidates in the design of
anti-cancer drugs targeting OATP2B1