Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.
Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes their effectiveness. This is typically the case in the development of cellular resistance to anticancer drugs. Inhibitors of these transporters are thus potentially useful tools to reverse this transporter-mediated cellular resistance to anticancer drugs and, eventually, to enhance the effectiveness of the treatment of patients with drug-resistant cancer. This review highlights the various types of inhibitors of several multidrug resistance-related ABC proteins, and demonstrates that the metabolism of inhibitors, as illustrated by recent data obtained for various natural compound inhibitors, may have considerable implications for their effect on drug transport and their potential for treatment of drug resistance.
Cnubben
Nicole H P
NH
TNO Quality of Life, PO Box 360, 3700 AJ Zeist, The Netherlands. Cnubben@pharma.tno.nl
Wortelboer
Heleen M
HM
van Zanden
Jelmer J
JJ
Rietjens
Ivonne M C M
IM
van Bladeren
Peter J
PJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D003524:Cyclosporins; D003986:Dibenzocycloheptenes; D011804:Quinolines; C095179:zosuquidar trihydrochloride; C070272:valspodar