Reversal of Multidrug Resistance by Natural Substances from Plants
Abstract:The multidrug resistance (MDR) proteins that belong to the ATP-binding cassette superfamily such as Pglycoprotein (P-gp) and MRP1, are present in a majority of human tumors and constitute an important cause of therapeutic failure. Selective inhibitors of the MDR-efflux proteins may improve the effectiveness of cancer chemotherapy. Their mechanism of action was believed to be a competition between resistance modifiers and drugs for the same binding site of P-gp. In our previous work we studied modulation of MDR in cancer cells expressing P-gp or MRP1 by selected carotenoids, flavonoids and extracts from medically important Chinese plants. Capsanthin and capsorubin, carotenoids isolated from paprika, were identified as potent P-gp inhibitors, while lycopene, lutein, antheraxanthin and violaxanthin induced moderate effects. Among flavonoids, effective modulators were rotenone, chrysin, phloretin and sakuranetin. Some chloroform extracts of Chinese herbs were also found to inhibit MDR efflux pumps. The effects of the modulators on Pgp activity were studied by measuring rhodamine 123 uptake in several cancer cells such as the human MDR1 genetransfected mouse lymphoma cells (L1210) and human breast cancer cells MDA-MB-231 expressing the MRP1 pump (HTB26). Additionally, the ability to alter biophysical properties of lipid bilayers by selected carotenoids was studied by differential scanning calorimetry. The antiproliferative effects as well as the MDR reversal activity of the studied compounds, applied in combination with anticancer drugs, were also discussed.
Keywords: 6a,12a-dehydroamorphigenin; ATP-binding cassette; Afrormosin, (+)-12a-hydroxyamorphigenin; Antheraxanthin; Astragalus; Atractylodes; Breast cancer resistance protein (BCRP); Cancer chemotherapy; Capsanthin; Capsicum annum L; Capsorubin; Carotenoids; Codonopsis; Diepoxy-β-carotene; Differential scanning calorimetry (DSC); Flavonoids; Ganoderma; Ginseng; Glutathione (GSH); HTB26 cells; Human breast- and colon cancer; Human cytomegalovirus (CMV); Ligustrum; Lutein; Lycopene; Lycophyll; MCF7/MDR1 cells; Mouse lymphoma cells transfected with human MDR1 gene; Multidrug resistance (MDR); Multiple Pharmacological Targets; Mutatochrome; Pglycoprotein (P-gp); Promyelocytic leukemia; Resistance modifiers; Rhodamine 123; Synergistic interactions; Traditional Chinese medicinal plants; Violaxanthin; Zeaxanthin; α- and b-cryptoxanthines; β-carotene
Document Type: Research Article
Affiliations: Institute of Medical Microbiology and Immunobiology, University of Szeged, H-6720 Szeged, Dom ter 10. Hungary.
Publication date: December 1, 2010