Anti-cancer drug-resistant tumors represent a major impediment to effective cancer therapy. One of the main pathways of cancer resistance is through the human multidrug resistance 1 (MDR1) trans- porter, which effluxes a relatively broad range of anti-cancer drugs and has been identified in ~50% of cancerous tumors. Despite findings from numerous studies, anti-cancer drug-transporter interactions and their molecular transport mechanisms are currently not well understood. To broaden our under- standing of anti-cancer drug transport by MDR1, there is a critical need to define the molecular and structural basis of anti-cancer drug transport. Our overall objective in the proposed studies is to define the molecular mechanisms of anti-cancer drug transport, to identify anti-cancer drug functional groups that interact with the transporter and to pinpoint the anti-cancer drug binding sites on the MDR1 transporter. Based on the known X-ray crystal structure of the mouse mdr3 transporter, the central hypothesis is that the anti-cancer drug transport rate by human MDR1 is controlled by multiple drugs binding in close proximity to the extracellular side of the transporter (near Y953). From this central hypothesis, two specific aims are proposed: The first specific aim is to define the mechanism of anti- cancer drug transport by MDR1 and to test the hypothesis that the anti-cancer drug transport rate is directly related to the number of anti-cancer drug binding sites. The second specific aim is to deter- mine the anti-cancer drug bound MDR1 conformations using atomic force microscopy (AFM) and to pinpoint the locations of anti-cancer drugs on MDR1 by NMR. These investigations have been de- signed to test the hypothesis that anti-cancer drugs with higher transport rates have binding sites relatively close to the extracellular side of the transporter. Ultimately, the successful completion of these studies will lead to the identification of specific anti-cancer drug properties that lead to MDR1- mediated transport. This information will allow us to design of novel fourth generation MDR1 trans- porter inhibitors and to make rational modifications of candidate and commercially available anti- cancer drugs to minimize MDR1-mediated efflux. Without the new knowledge from the completion of this research, effective strategies for rationally designing drugs that can effectively overcome MDR1- mediated cancer resistance are likely to remain limited and MDR1-mediated drug resistance will re- main a leading cause of cancer resistance and mortality.
In the U.S., cancer claims over 500,000 victims annually with greater than a million patients undergo- ing treatment. Many cancer victims unfortunately develop drug resistant tumors, in large part because their tumors are able to effectively eliminate the anti-cancer drugs with a biological pump that is known as the multidrug resistance (MDR) transporter. The successful completion of the proposed studies on the MDR transporter will produce rapid and innovative approaches that are critical for overcoming cancer resistance, will accelerate anti-cancer drug development, and will improve the ef- fectiveness of current cancer treatments.
| Karasik, Agnes; Ledwitch, Kaitlyn Victoria; Arányi, Tamás et al. (2018) Boosted coupling of ATP hydrolysis to substrate transport upon cooperative estradiol-17-?-D-glucuronide binding in a Drosophila ATP binding cassette type-C transporter. FASEB J 32:669-680 |
| Gibbs, Morgan E; Wilt, Laura A; Ledwitch, Kaitlyn V et al. (2018) A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein. J Pharm Sci 107:1937-1947 |
| Roberts, Arthur G; Gibbs, Morgan E (2018) Mechanisms and the clinical relevance of complex drug-drug interactions. Clin Pharmacol 10:123-134 |
