Developing Natural Product Modulators to Overcome Multidrug Resistance in Cancer Chemotherapy

Cancer remains as one of the leading causes of death globally, and successful cancer treatment has thus become one of the major challenges to modern medicine. One of the major obstacles to successful cancer chemotherapy is the development of multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (MDR1, P-glycoprotein) and/or ABCG2 (BCRP, MXR). Functional ABCB1 and ABCG2 can confer cross-resistance to multiple drugs of differing chemical classes by actively effluxing cytotoxic drugs out of cancer cells, significantly reducing the intracellular accumulation of these drugs and resulting in MDR. Moreover, ABCB1 and ABCG2 are highly expressed in various tissues including the intestine, liver, kidney, placenta, adrenal gland and blood-brain barrier (BBB), protecting the body from xenobiotics and harmful drugs. Collectively, these two transporters confer resistance to, and by affecting the oral bioavailability, distribution and elimination, limit the use of most conventional anticancer agents and many newly developed targeted drugs, hence hampers the overall effectiveness of chemotherapeutic agents. Consequently, re-sensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 and/or ABCG2 has been considered as the most attractive strategy to overcome transporter-mediated MDR in cancer patients. For decades, the task of finding a suitable modulator of ABCB1 and/or ABCG2 has been hindered mostly by the complex pharmacokinetics and the high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively non-toxic nature of natural products, developing potential modulator of ABC transporters from natural sources is particularly valuable. It was reported that approximately 80% of cancer patients use natural products in combination with conventional anticancer drugs or as nutritional supplements to enhance the effectiveness of anticancer agents and increase immune response, or simply to reduce unwanted side effects caused by the anticancer drugs themselves. Many non-toxic natural products or metabolites, including various extracts and active components ranging from plants and fungi to marine organisms have already been investigated to overcome MDR in cancer cells with some success, but without systematic search being conducted. With that in mind, we developed a fluorescent cell-based high-throughput drug screening (HTS) system that can rapidly and accurately identify chemicals from compound libraries that are capable of inhibiting the efflux function of human ABCB1 and/or ABCG2. From a compound library consisting of 502 purified bioactive natural products, we have identified many candidate compounds (57 for ABCB1 and 43 for ABCG2) that have great potential to be repositioned as clinically active modulators that can reverse MDR mediated by ABCB1 or ABCG2 in human cancer cells.We intend to fully characterize and optimize these candidates sequentially in a series of in vitro and in vivo experiments, which will take years to complete. During the study, we intend to carry out additional HTS of 80 traditional Chinese medicine (TCM) formulations in attempt to evaluate the modulatory potentials of these TCMs.

Project ID:PB10608-3646
External Project ID:MOST106-2320-B182-017