Is ASCT2 a suitable vector for the selective delivery of anticancer drugs? Modification of glutamine at either the carboxylate or the side chain hinders binding and transport.

The Alanine, Serine, and Cysteine Transporter 2 (ASCT2) transports glutamine into cells and is upregulated in many cancers. Attachment to glutamine to enable ASCT2 to transport anticancer agents into cells has been proposed, but the impact of such modifications is a critical determinant of the potential of this strategy. Transport via ASCT2 of two glutamine analogues modified in ways that reflect possible mechanisms for attaching anticancer agents was studied. The aim was to determine if the modification of glutamine interferes with its transport via ASCT2 and thereby establish whether the conjugation of drugs to glutamine can facilitate the accumulation of anticancer drugs in cancer cells. L-theanine and a glutamine derivative modified at the carboxylate (7) were applied to Xenopus laevis oocytes expressing ASCT2. Two-electrode voltage clamp electrophysiology was used to measure substrate-elicited currents over a range of membrane potentials. Compound 7 was identified as neither a substrate nor an inhibitor while L-theanine was identified as an inhibitor of ASCT2. Thus, modification of glutamine in these ways prevents it from acting as a substrate and suggests that ASCT2 may not be a suitable target for delivery of anticancer drugs attached via either the carboxylate or side chain positions.