Downregulation of mdr1 and 1 abcg2 genes is a mechanism of

ML CUESTAS,; CASTILLO, AI,; A SOSNIK; MATHET, VL

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2012

0960-894X

The ability of cells to acquire resistance to multiple pharmaceuticals, namely 3 multidrug resistance (MDR), is often mediated by the over-expression of effluxmultidrug resistance (MDR), is often mediated by the over-expression of efflux 4 transporters of the ATP-binding cassette (ABC) superfamily; e.g., P-glycoproteintransporters of the ATP-binding cassette (ABC) superfamily; e.g., P-glycoprotein 5 (P-gp or MDR1), breast cancer resistance protein (BCRP), and multidrug(P-gp or MDR1), breast cancer resistance protein (BCRP), and multidrug 6 resistance-associated protein MRP1. ABCs pump drug molecules out of cellsresistance-associated protein MRP1. ABCs pump drug molecules out of cells 7 against a concentration gradient, reducing their intracellular concentration. Theagainst a concentration gradient, reducing their intracellular concentration. The 8 ability of polymeric amphiphiles to inhibit ABCs as well as the cellular pathwaysability of polymeric amphiphiles to inhibit ABCs as well as the cellular pathways 9 involved in the inhibition has been extensively investigated. This work investigatedinvolved in the inhibition has been extensively investigated. This work investigated 10 for the first time the effect of branched poly(ethylene oxide)-poly(propylene oxide)for the first time the effect of branched poly(ethylene oxide)-poly(propylene oxide) 11 block copolymers (poloxamines) on the levels of mRNA encoding for MDR1, BCRPblock copolymers (poloxamines) on the levels of mRNA encoding for MDR1, BCRP 12 and MRP1, in a human hepatoma cell line (Huh7). Copolymers with a broad rangeand MRP1, in a human hepatoma cell line (Huh7). Copolymers with a broad range 13 of molecular weights and hydrophilic-lipophilic balances were assayed. Resultsof molecular weights and hydrophilic-lipophilic balances were assayed. Results 14 confirmed the down-regulation of mdr1 and abcg2 genes. Conversely, the mrp1confirmed the down-regulation of mdr1 and abcg2 genes. Conversely, the mrp1 15 gene was not affected. These findings further support the versatility of thesegene was not affected. These findings further support the versatility of these 16 temperature- and pH-responsive copolymers to overcome drug resistance intemperature- and pH-responsive copolymers to overcome drug resistance in 17 cancer and infectious diseases.cancer and infectious diseases.