Sheereen Majd, Ph.D. Assistant Professor, Department of Bioengineering, Pennsylvania State University

Functional Studies of Multidrug Resistance Transporters at Single-Protein Level

Abstract

Currently, successful treatment of human cancers is severely hindered by the resistance that
cancerous cells develop against a wide range of chemotherapeutic drugs (multidrug resistance (MDR) phenomenon). A group of membrane transporters that actively pump these drugs out of cells are believed to be a major cause of this resistance. Most of the clinically used therapeutics interact with these transporters and consequently lose their effectiveness or produce undesired side effects. Despite years of research on these pumps and development of a number of modulators for them, there has been no significant progress in overcoming clinical MDR. New and highly effective strategies to modulate MDR transporters are, hence, urgently needed. Development of such modulators requires a detailed understanding of the mechanism of function of these proteins. To this end, we propose to develop a highly sensitive fluorescent assay that allows studying several different aspects of MDR transporters at the same time under defined conditions. Using this assay, we aim to conduct a mechanistic investigation of the biochemical and biophysical parameters (such as membrane fluidity) that regulate the transport activity of these proteins. Findings of this study may accelerate the rational design of new modulators for MDR pumps to overcome clinical MDR.

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