ABC Transporters as Target for RNA Interference-mediated Reversal of Multidrug Resistance: Implications in Microorganisms
from: ABC Transporters in Microorganisms: Research, Innovation and Value as Targets against Drug Resistance (Edited by: Alicia Ponte-Sucre). Caister Academic Press, U.K. (2009)
Drug resistance is a common clinical problem that occurs in patients suffering from infectious diseases, and in patients suffering from cancer. Prokaryotic and eukaryotic microorganisms as well as neoplastic cells are often found to be refractory to multiple structurally unrelated compounds used during chemotherapy. This phenomenon has been termed multidrug resistance (MDR). In both, prokaryotic and eukaryotic organisms, MDR is frequently associated with overexpression of trans-membrane xenobiotic transport molecules belonging to the superfamily of ATP-binding cassette (ABC)-transporters. Inhibition of ABC-transporters by low-molecular weight compounds has been extensively investigated in cancer patients; however, the clinical results have been disappointing. Consequently, innovative experimental therapeutic strategies for overcoming MDR are urgently needed and are under investigation. These strategies include the application of the novel RNA interference (RNAi) technology. Various RNAi strategies have been applied to reverse MDR in different tumor models in vitro and in vivo indicating that this technology is tremendously effective in reversing ABC-transporter-mediated MDR in cancer and is therefore a promising strategy for overcoming MDR by gene therapeutic applications. The RNAi pathway is restricted to eukaryotic cells. This observation suggests that the RNAi technology appears to be only useful for reversal of ABC-transporter-mediated MDR in eukaryotic infection disease-causing microorganisms, such as parasites. However, besides the data that has been obtained using this technology in pathogenic parasites, efforts have been made to trigger gene silencing by RNAi in prokaryotic cells. Should this approach be successful in the future, RNAi technology could also be considered for overcoming MDR in infection diseases mediated by prokaryotic pathogens read more ...