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Dynamic Mechanisms Of Multidrug Resistance In Human Cancers And Gram Negative Pathogens, Lauren Ammerman
Dynamic Mechanisms Of Multidrug Resistance In Human Cancers And Gram Negative Pathogens, Lauren Ammerman
Biological Sciences Theses and Dissertations
This dissertation focuses upon dynamic agents of multidrug resistance (MDR). We used a combination of in silico and in vitro techniques to investigate two membrane transporters that confer MDR – P-glycoprotein, which confers MDR in human cancers, and MtrD, which confers MDR in Neisseria gonorrhoeae. Inhibitors targeting both proteins have tremendous potential for use as co-therapeutics in the treatment of multidrug resistant cancers, or of multidrug resistant infections. However, previously identified inhibitors of P-gp have failed clinical trials due to off-target effects and associated toxicities. Furthermore, the molecular mechanism of antibiotic transport by MtrD is poorly understood, and this dearth …
Mechanistic Studies Of Drug-Like Inhibitors Of P-Glycoprotein Using Atpase Assays, Electron Spin Resonance Spectroscopy And Cancer Cell Models, Gang Chen
Biological Sciences Theses and Dissertations
Multidrug resistance (MDR) in cancer and other diseases is frequently associated with transmembrane efflux proteins, one of which is P-glycoprotein (P-gp). Over-expression of P-gp in cancer cells increases the efflux of therapeutic drugs rendering them ineffective. In order to re-sensitize multidrug resistant cancers to chemotherapy, we have found potential inhibitors of P-gp by in silico screening methods, and several of these inhibitors were shown to successfully overcome MDR in the drug resistant DU145TXR prostate cancer cell line. The best of the identified hit compounds were further investigated with regard to the mechanism of inhibition using ATPase activity assays and electron …