The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis.

摘要: Members of the ATP-binding cassette (ABC) transporters including P-glycoprotein (Pgp/ABCB1), multidrug resistance proteins (MRPs/ABCC) as well breast cancer protein (BCRP/ABCG2) function ATP-dependent drug efflux transporters, which form a unique defense network against multiple chemotherapeutic drugs and cellular toxins. Among antitumor agents is important group folic acid antimetabolites known antifolates. Antifolates such methotrexate (MTX), pemetrexed raltitrexed exert their cytotoxic activity via potent inhibition folate-dependent enzymes essential for purine pyrimidine nucleotide biosynthesis thereby block DNA replication. Overexpression MRPs BCRP confers upon malignant cells to various hydrophilic lipophilic Apart from central role in mediating antifolates other anticancer drugs, have been recently shown transport naturally occurring reduced folates. This was inferred complementary systems follows: (a) Cell-free uptake radiolabeled folate/MTX into purified inside-out membrane vesicles stable transfectants and/or overexpressing these (b) Decreased accumulation cultured tumor (c) In vivo rodent models Eisi hyperbillirubinemic rats (EHBR) that hereditarily lack MRP2 canalicular display bile highly deficient folate cofactors MTX, when compared with wild type Sprague-Dawley (SD) rats. all cases, folate/antifolate functioned high capacity, low affinity ATP-driven exporters. While mechanism retention (anti)folates mediated (anti)folylpolyglutamylation, certain MRP5 (ABCC5) were both mono-, di- triglutamate derivatives MTX acid. Furthermore, overexpression has result decreased pools, whereas loss ABC transporter expression brought about significant expansion intracellular pool. The latter finding implications antifolate-based chemotherapy an augmented pool results level Hence, aims present review are: To summarize discuss cumulative evidence supporting functional superfamily mediate antifolates, describe evaluate recent data suggesting regulation homeostasis under replete deplete conditions. novel developments future perspectives regarding identification antifolate target mechanisms action, rationally designed emerging combinations containing along receptor tyrosine kinase inhibitors are being discussed.