A Systematic Approach to Identify Novel Inhibitors of Multidrug-Resistance Associated Proteins from Purified Natural Products: Drug Screening, in Vitro and in Vivo Model Systems

Cancer remains as one of the leading causes of death globally, and in Taiwan. One of the major obstacles in modern chemotherapy is often associated with the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (MDR1, P-glycoprotein) and/or ABCG2 (BCRP, MXR) in cancer cells. ABCB1 and ABCG2 are membrane proteins that generate energy from ATP hydrolysis to actively efflux cytotoxic anticancer agents out of cancer cells, thus reducing the intracellular drug accumulation, leading to a multidrug resistance (MDR) phenotype. Currently, direct inhibition of ABCB1 and ABCG2 appears to be the most effective way to resolve MDR, and the development of selective and potent synthetic inhibitors for ABCB1 and ABCG2 has been ongoing for years. Unfortunately, problems associated with high intrinsic toxicity of these synthetic agents have resulted in unfavorable clinical trials. Considering that a large number of natural products and their derivatives have been investigated globally for their ability to prevent, inhibit and reverse the progression of cancer, and that approximately 80% of cancer patients use natural products in combination with conventional anti-cancer drugs either as nutritional supplements or as complementary or alternative medicines, we decided to evaluate the potential of utilizing purified natural product modulators to enhance/restore the chemosensitivity of MDR cancers to chemotherapeutic drugs. Previously, we have discovered several novel, purified natural products that interacted strongly with ABCB1 and/or ABCG2. In this study, we intend to fully characterize all thirteen candidate modulators for their ability to modulate the function and/or expression of ABCB1 and ABCG2 in cancers, using both in vitro and in vivo MDR model systems in three years. We believe that these biologically active candidate natural modulators have great potential to be further developed into potent chemosensitizers in combination therapy for the treatment of MDR cancers and improve the clinical outcome in patients with ABC transporter-positive MDR cancers in future clinical practices.

Project ID:PB10901-3525
External Project ID:MOST108-2320-B182-038-MY3