Enhanced intracellular accumulation of 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 anti-cancer agents are expelled from cancer cells, makes it necessary to develop methods that will reliably increase the accumulation of anti-cancer 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 ATB(0,+) played a role, whereas the dipeptide 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 favour of a prodrug concept that can improve intracellular accumulation and take advantage of amino acid transporters without significantly inducing multiple-drug resistance.
National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
Eun-Young
EY
Kwak
Won-Sik
WS
Shim
Ji-Eun
JE
Chang
Saeho
S
Chong
Dae-Duk
DD
Kim
Suk-Jae
SJ
Chung
Chang-Koo
CK
Shim
D026924:Amino Acid Transport System A / Q000378:metabolism; D026962:Amino Acid Transport System ASC / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism*; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004952:Esters; D057809:HEK293 Cells; D006801:Humans; D000077146:Irinotecan; D015778:Minor Histocompatibility Antigens; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism; D014633:Valine / Q000378:metabolism*
D026924:Amino Acid Transport System A; D026962:Amino Acid Transport System ASC; D026905:Amino Acid Transport Systems; D000970:Antineoplastic Agents; D004952:Esters; D015778:Minor Histocompatibility Antigens; D011355:Prodrugs; C420506:SLC1A5 protein, human; C445761:SLC38A1 protein, human; C498797:SLC38A2 protein, human; D000077146:Irinotecan; D014633:Valine; D002166:Camptothecin