Harnessing drug resistance: using ABC transporter proteins to target cancer cells.
The ATP-binding cassette (ABC) class of proteins is one of the most functionally diverse transporter families found in biological systems. Although the abundance of ABC proteins varies between species, they are highly conserved in sequence and often demonstrate similar functions across prokaryotic and eukaryotic organisms. Beginning with a brief summary of the events leading to our present day knowledge of ABC transporters, the purpose of this review is to discuss the potential for utilizing ABC transporters as a means for cellular glutathione (GSH) modulation. GSH is one of the most abundant thiol antioxidants in cells. It is involved in cellular division, protein and DNA synthesis, maintenance of cellular redox status and xenobiotic metabolism. Cellular GSH levels are often altered in many disease states including cancer. Over the past two decades there has been considerable emphasis on methods to sensitize cancer cells to chemotherapeutics and radiation therapy by GSH depletion. We contend that ABC transporters, particularly multi-drug resistant proteins (MRPs), may be used as therapeutic targets for applications aimed at modulation of GSH levels. This review will emphasize MRP-mediated modulation of intracellular GSH levels as a potential alternative and adjunctive approach for cancer therapy.
Leitner
Heather M
HM
Department of Pharmaceutical Sciences, University of Colorado, Health Sciences Center, Denver, CO, USA.
Kachadourian
Remy
R
Day
Brian J
BJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010084:Oxidation-Reduction
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D005978:Glutathione