RT Journal Article
SR Electronic
T1 Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin Induced CYP3A4 and MDR1 Gene Expression
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.114587
DO 10.1124/mol.118.114587
A1 Kodye L Abbott
A1 Chloe S Chaudhury
A1 Aneesh Chandran
A1 Saraswathi Vishveshwara
A1 Zdenek Dvorak
A1 Eva Jiskrova
A1 Karolina Poulikova
A1 Barbora Vyhlidalova
A1 Sridhar Mani
A1 Satyanarayana R Pondugula
YR 2019
UL http://molpharm.aspetjournals.org/content/early/2019/01/08/mol.118.114587.abstract
AB Activation of human pregnane X receptor (hPXR) has been associated with induction of chemoresistance. It has been proposed that such chemoresistance via cytochromes P450/drug transporters can be reversed with use of antagonists that specifically abrogate agonist-mediated hPXR activation. Unfortunately, proposed antagonists lack specificity and appropriate pharmacological characteristics that allow these features to be active in the clinic. We propose that, ideally, a hPXR antagonist would be a cancer drug itself that is part of a "cancer drug cocktail&rdquo", and effective as a hPXR antagonist at therapeutic concentrations. Belinostat (BEL), a histone deacetylase inhibitor approved for the treatment of relapsed/refractory peripheral T-cell lymphoma, and often used in combination with chemotherapy, is an attractive candidate based on its hPXR ligand-like features. We sought to determine whether these features of BEL might allow it to behave as an antagonist in combination chemotherapy regimens that include hPXR activators. BEL represses agonist-activated hPXR target gene expression at its therapeutic concentrations in human primary hepatocytes and LS174T human colon cancer cells. BEL repressed rifampicin-induced gene expression of CYP3A4 and MDR1, as well as their respective protein activities. BEL decreased rifampicin-induced resistance to SN-38, the active metabolite of irinotecan, in LS174T cells. This finding indicates that BEL could suppress hPXR agonist-induced chemoresistance. BEL attenuated the agonist-induced SRC-1 interaction with hPXR, and together with molecular docking studies, suggests that BEL directly interacts with multiple sites on hPXR. Taken together, our results suggest that BEL, at its clinically relevant therapeutic concentration, can antagonize hPXR agonist-induced gene expression and chemoresistance.