Reversal of Multidrug Resistance by Natural Substances from Plants

Q.      Wang; K.      Michalak; O.      Wesolowska; J.      Deli; P.      Molnar; J.      Hohmann; J.      Molnar; H.      Engi

doi:10.2174/156802610792928103

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: Human cytomegalovirus (CMV), Ganoderma, Atractylodes, Codonopsis, Ginseng, Ligustrum, Astragalus, Glutathione (GSH), 6a,12a-dehydroamorphigenin, Afrormosin, (+)-12a-hydroxyamorphigenin, Capsicum annum L., Multiple Pharmacological Targets, Differential scanning calorimetry (DSC), MCF7/MDR1 cells, Diepoxy-β-carotene, Mutatochrome, HTB26 cells, α- and b-cryptoxanthines, Antheraxanthin, Zeaxanthin, Lutein, Lycopene, Violaxanthin, Lycophyll, Capsorubin, Capsanthin, Rhodamine 123, Cancer chemotherapy, β-carotene, Promyelocytic leukemia, Breast cancer resistance protein (BCRP), Pglycoprotein (P-gp), ATP-binding cassette, Traditional Chinese medicinal plants, Synergistic interactions, Resistance modifiers, Multidrug resistance (MDR), Mouse lymphoma cells transfected with human MDR1 gene, Human breast- and colon cancer, Flavonoids, Carotenoids