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 spin resonance spectroscopy (ESR). Using a spin-labeled ATP analog and ESR spectroscopy, we assessed the effects of the identified inhibitors on ATP binding to P-gp. In the ATPase activity assays, it was found that the environment of P-gp is extremely important for drug discovery efforts using purified membrane proteins.
Biochemistry, Biophysics, Life Sciences
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Chen, Gang, "Mechanistic Studies of Drug-Like Inhibitors of P-glycoprotein Using ATPase Assays, Electron Spin Resonance Spectroscopy and Cancer Cell Models" (2021). Biological Sciences Theses and Dissertations. 10.