N-methylation of anthracyclines modulates their cytotoxicity and pharmacokinetic in wild type and multidrug resistant cells
| Autor: | L. Gaté, Patrick Couvreur, H Tapiero, G Nguyen-Ba |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Anthracycline
Cell Survival Antineoplastic Agents Biology Pharmacology Methylation Mice Structure-Activity Relationship Tumor Cells Cultured Animals Anthracyclines ATP Binding Cassette Transporter Subfamily B Member 1 Cytotoxicity P-glycoprotein Wild type Biological Transport General Medicine In vitro Drug Resistance Multiple Multiple drug resistance Drug Resistance Neoplasm biology.protein Efflux Leukemia Erythroblastic Acute Multidrug Resistance-Associated Proteins Cell Division |
| Zdroj: | Biomedicinepharmacotherapy = Biomedecinepharmacotherapie. 57(7) |
| ISSN: | 0753-3322 |
| Popis: | Anthracyclines are the most commonly used classes of anticancer agents in chemotherapy. Development of resistance to these molecules is one of the major reasons for treatment failure. The overexpression of the membrane transporter P-glycoprotein (P-gp) is among the principal mechanisms involved in this phenomenon. This pump, which is responsible for the multidrug resistance (MDR) phenotype, decreases the toxicity of a wide range of unrelated anticancer drugs by increasing their cellular efflux. Structure-activity relationship experiments have shown that the positively charged amino group of the anthracyclines could be responsible for their transport by P-gp. Here, we used three new anthracyclines that shared the same chromophore but differed by the degree of N -methylation of their sugar moiety. Oxaunomycin (OXN) possessed a non-methylated amino group, while LB-1 was monomethylated and β-clamycin T (BCT) was dimethylated. In sensitive cells (FLC), reduced cytotoxicity was related to the level of N -methylation; whereas in resistant cells (DOX-RFLC 1 and DOX-RFLC 2 ) overexpressing different levels of P-gp, increased N -methylation enhanced anthracycline cytotoxicity. Decreased resistance in DOX-RFLCs was associated with an increased drug accumulation due to a reduced cellular efflux. As expected, the MDR modulator verapamil decreased resistance to these anthracyclines by increasing the cellular accumulation. These results suggest that N -methylation of anthracyclines circumvents resistance by diminishing drug transport by P-gp in MDR-positive cells. These observations could be the consequence of the steric hindrance created by the methyl group(s) which may impair the interaction between the positively charged amino group and the active site of P-gp. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect