Modulation of P-Glycoprotein-Mediated Multidrug Resistance by Synthetic and Phytochemical Small Molecules, Monoclonal Antibodies, and Therapeutic Nucleic Acids

Multidrug resistance of malignant tumors severely hampers their successful treatment frequently leading to fatal consequences for affected patients. During the past three decades, many efforts have been spent to develop strategies to overcome multidrug resistance. Many chemical compounds have been shown to inhibit the drug efflux of the multidrug-resistance-mediating P-glycoprotein. Chemical P-glycoprotein inhibitors are from the classes of calcium channel antagonists, calmodulin inhibitors, cyclosporins, antiarrhythmics, hormones, antimalarials, antibiotics, detergents, beta-blockers, antidepressants, blood pressure lowering indol alkaloids, aerobic glycolysis inhibitors, HIV-protease inhibitors, antimycotics, and others. More recently, chemical compounds from medicinal plants or food were also identified as potent P-glycoprotein inhibitors. P-glycoprotein-inhibiting phytochemicals are from diverse classes, such as flavonoids, nonflavonoid polyphenols, alkaloids, steroids, stilbenes, monoterpenoids, dipterpenoids, triterpenoids, triterpene saponines, lignans, flavolignans, polyketides, carotenoids, and others. In addition to chemical synthetic or natural small molecules several other therapeutic strategies have been devised, e.g. monoclonal antibodies blocking drug efflux, immunotoxins specifically targeting and killing multidrug-resistant cells and therapeutic nucleic acids downregulating the P-glycoprotein encoding the MDR1 gene and resensitizing tumor cells to anticancer drugs. We give an overview of our own research with in vitro and in vivo tumor models in the context of the worldwide efforts to overcome multidrug resistance.