Why the xanthine derivatives are used to study of P-glycoprotein-mediated multidrug resistance in L1210/VCR line cells

• Published in: General physiology and biophysics Vol. 29; no. 3; p. 215
• Main Authors: Dočolomanský, Peter, Boháčová, Viera, Barančík, Miroslav, Breier, Albert
• Format: Journal Article
• Language: English
• Published: Slovakia 01.09.2010
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Binding Sites; Drug Resistance, Neoplasm; Hydrogen Bonding; Leukemia L1210 - drug therapy; Leukemia L1210 - metabolism; Mice; Structure-Activity Relationship; Xanthines - chemistry; Xanthines - metabolism; Xanthines - pharmacology
• ISSN: 0231-5882
• DOI: 10.4149/gpb_2010_03_215

There is generally well known that various xanthines occur frequently in natural products, e.g. black coffee, black tea, green tea, natural dyes etc. Xanthine molecules are good tolerated and metabolised by organisms. Moreover, natural xanthines and/or sythesized xanthines may recall a lot positive affects (hemorheologic properties, anti-inflammatory properties, tracheal smooth muscle relaxant, positive chronotropic and central nervous system-stimulating, etc.) and may even induce a quantity of changes on the molecular level (inhibition of cyclic nucleotide phosphodiesterases, inhibition of the synthesis of tumor necrosis factor (TNF-alpha), cellular Ca(2+) homeostasis, etc.). In our previous paper we showed that some xanthine derivatives (pentoxifylline and its derivatives) depress P-glycoprotein (P-gp) mediated multidrug resistance of the mouse leukemic cells. Other authors, first of all Sadzuka and co-workers, confirm this usefulness of long side substituted xanthines as biochemical modulators. However, the mechanism of molecular action of xanthine derivatives has not been clarified. One of the possible ways to chemosensitize the cancer cells is direct competiting in defence mechanism - inhibition of efflux pump (P-gp). Interaction of xanthine derivatives with binding site of P-gp is a question which could be solved by experiment; although, molecular modelling may clear up this matter. But, each dynamic and static program for molecular simulation of P-gp action is dividing on input variable, considering mechanistic view of insight drug transport.