Enhanced intracellular accumulation of SN-38, a non-nucleoside anti-cancer agent, via increased uptake of its valine ester prodrug through amino acid transporters

The phenomenon known as multiple-drug resistance, whereby anticancer agents are expelled from cancer cells, makes it necessary to develop methods that will reliably increase the accumulation of anticancer agents within cancer cells. To accomplish this goal, a new model compound, Val-SN-38, was synthesized by introducing valine to SN-38, an active ingredient of irinotecan. Val-SN-38 improved intracellular accumulation approximately 5-fold in MCF7 cells, compared with SN-38, and rather than changes in membrane permeability, the amino acid transporter ATB0,+ played a role, whereas the di-peptide transporter PEPT1 did not. Other sodium-dependent amino acid transporters, namely ATA1, ATA2, and ASCT2, were unexpectedly involved in the uptake of Val-SN-38 as well. The efflux of Val-SN-38 by major efflux transporters was variably changed, but not significantly. In summary, the enhanced accumulation of Val-SN-38 in cancer cells was due to augmented uptake via various amino acid transporters. The results of the present study make a compelling argument in favor of a prodrug concept that can improve intracellular accumulation and take advantage of amino acid transporters without significantly inducing multiple-drug resistance.Docto