Downregulation of mdr1 and abcg2 genes is a mechanism of inhibition of efflux pumps mediated by polymeric amphiphiles

• Published in: Bioorganic & medicinal chemistry letters 2012-11, Vol.22 (21), p.6577-6579
• Main Authors: Cuestas, María L., Castillo, Amalia I., Sosnik, Alejandro, Mathet, Verónica L.
• Format: Article
• Language: English
• Subjects: ABC transporters; Amines - chemistry; Amines - pharmacology; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; breast neoplasms; Cell Line, Tumor; composite polymers; Down-Regulation - drug effects; drugs; ethylene oxide; gene expression regulation; genes; hepatoma; Humans; Indexing in process; infectious diseases; Inhibition of ATP-binding cassette pumps; mdr1, mpr1 and abcg2 genes; Medical sciences; messenger RNA; molecular weight; multiple drug resistance; Neoplasm Proteins - genetics; Oxamic Acid - chemistry; Oxamic Acid - pharmacology; Pharmacology. Drug treatments; Poloxamines; Polymerase Chain Reaction; propylene oxide; Surface-Active Agents - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.09.012

The ability of cells to acquire resistance to multiple pharmaceuticals, namely multidrug resistance (MDR), is often mediated by the over-expression of efflux transporters of the ATP-binding cassette (ABC) superfamily; for example P-glycoprotein (P-gp or MDR1), breast cancer resistance protein (BCRP or ABCG2), and multidrug resistance-associated protein MRP1. ABCs pump drug molecules out of cells against a concentration gradient, reducing their intracellular concentration. The ability of polymeric amphiphiles to inhibit ABCs as well as the cellular pathways involved in the inhibition has been extensively investigated. This work investigated for the first time the effect of branched poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamines) on the levels of mRNA encoding for MDR1, BCRP and MRP1, in a human hepatoma cell line (Huh7). Copolymers with a broad range of molecular weights and hydrophilic-lipophilic balances were assayed. Results confirmed the down-regulation of mdr1 and abcg2 genes. Conversely, the mrp1 gene was not affected. These findings further support the versatility of these temperature- and pH-responsive copolymers to overcome drug resistance in cancer and infectious diseases.