Project Details
Abstract
ATP-binding cassette (ABC) drug transporter ABCB1 (MDR1, P-glycoprotein) and/or ABCG2 (BCRP, MXR) are membrane proteins that generate energy from ATP hydrolysis to actively efflux cytotoxic drugs out of cancer cells and reduce the intracellular accumulation of these drugs significantly, resulting in cross-resistance to multiple drugs of differing chemical classes, a phenomenon called multidrug resistance (MDR). MDR caused by the overexpression of ABCB1 and ABCG2 remains a major obstacle to successful cancer chemotherapy to date. 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. As a result, a majority of conventional chemotherapeutic agents are affected by the transport function of ABCB1 and/or ABCG2, such as reduced oral bioavailability, distribution and elimination of these drugs. Currently, the most effective way to re-sensitize MDR cancer cells is through direct and transient inhibition of the function and/or expression of ABCB1 and ABCG2. However, the major obstacles with using synthetic compounds as clinically active inhibitors are often associated with the cost and the unforeseen intrinsic toxicity of these compounds. Therefore, we have been evaluating the possibility of repositioning (drug re-purposing) therapeutic drugs with known biological properties for the purpose of re-sensitizing MDR cancer cells and improve clinical outcome in patients with ABC transporter-positive MDR cancers in future clinical practices. We have recently identified 14 tyrphostins, which are protein tyrosine kinase inhibitors of the tyrphostin family, that interact strongly with ABCB1 and/or ABCG2, indicating that they are excellent candidates to be repositioned as potent modulators of ABCB1 and ABCG2. Therefore, by performing a series of pharmacological and biochemical studies, we intend to determine the potential of these candidate tyrphostins, both in in vitro and in vivo MDR model systems, on reversing MDR mediated by ABCB1 and/or ABCG2 in human cancer cells.
Project IDs
Project ID:PC10707-0135
External Project ID:MOST107-2320-B182-017
External Project ID:MOST107-2320-B182-017
Status | Finished |
---|---|
Effective start/end date | 01/08/18 → 31/07/19 |
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.