Repurposing FDA Approved Drugs to Antagonize Pregnane X Receptor Mediated Chemoresistance
Type of DegreePhD Dissertation
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Human pregnane X receptor (hPXR) is an orphan nuclear receptor that regulates key drug metabolism enzymes (DMEs) and drug-transport proteins (DTPs), including Cytochrome p450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1), respectively. hPXR is activated by a diverse group of xenobiotics, including anticancer drugs. Activation of hPXR has been associated with induction of chemoresistance via upregulation of CYP3A4 and MDR1. CYP3A4 and MDR1 together contribute to the metabolism and disposition of more than 50% of clinically active drugs. Therefore, during multidrug chemotherapy, drug induction of hPXR-mediated CYP3A4 and MDR1, can affect the therapeutic response of co-administered drugs, leading to chemoresistance. It has been shown that such hPXR-mediated chemoresistance, via upregulated DMEs and DTPs, can be reversed with use of an hPXR antagonists that specifically abrogate agonist-mediated hPXR activation. However, proposed hPXR inhibitors and antagonists fall short of their clinical utility, as it is unlikely for them to achieve in vivo concentration levels to antagonize hPXR without causing severe unacceptable toxicity. This negative attribute could be overcome if an FDA approved drug could be repurposed as an hPXR antagonist. We propose that, ideally, an hPXR antagonist would be an FDA approved drug that can be part of a “cancer drug cocktail”, and effective as an hPXR antagonist at therapeutic concentrations. Therefore, we screened a panel of FDA approved drugs to identify potential hPXR antagonists. From the primary screening, we selected two promising candidates, Belinostat (BEL) and Gefitinib (GEF). Both BEL and GEF were further tested to determine their ability to antagonize the agonist-activated hPXR at their therapeutically relevant concentrations. BEL, a histone deacetylase inhibitor approved for the treatment of relapsed/refractory peripheral T-cell lymphoma, repressed the hPXR agonist-induced gene expression of CYP3A4 and MDR1, as well as their respective protein activities. BEL also suppressed the hPXR agonist-induced chemoresistance. Similarly, GEF, an EGFR inhibitor for the treatment of advanced non-small cell lung cancer, repressed the hPXR agonist-induced CYP3A4 gene expression. Mechanistically, both BEL and GEF attenuated the agonist-induced SRC-1 interaction with hPXR, and together with molecular docking studies, suggest that BEL and GEF directly interact with multiple sites on hPXR. Taken together, our results suggest that BEL and GEF, at their clinically relevant therapeutic concentrations, can antagonize hPXR agonist-induced gene expression. Thus, BEL and GEF could be potential candidates to overcome hPXR agonists-induced chemoresistance during combination chemotherapies.
- Abbott_Kodye_PhD Dissertation_Fall 2019.pdf