Abbott, KL and Chaudhury, CS and Chandran, A and Vishveshwara, S and Dvorak, Z and Jiskrova, E and Poulikova, K and Vyhlidalova, B and Mani, S and Pondugula, SR (2019) Belinostat, at its clinically relevant concentrations, inhibits rifampicin-induced CYP3A4 and MDR1 gene expressions. In: Molecular Pharmacology, 95 (3). pp. 324-334.
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Abstract
Activation of human pregnane X receptor (hPXR) has been associated with induction of chemoresistance. It has been proposed that such chemoresistance via cytochrome P450/drug transporters can be reversed with the use of antagonists that specifically abrogate agonist-mediated hPXR activation. Unfortunately, proposed antagonists lack the specificity and appropriate pharmacological characteristics that allow these features to be active in the clinic. We propose that, ideally, an hPXR antagonist would be a cancer drug itself that is part of a “cancer drug cocktail” and effective as an 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 multidrug resistance protein 1, 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 steroid receptor coactivator-1 interaction with hPXR, and, together with molecular docking studies, the study 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.
| Item Type: | Journal Article |
|---|---|
| Publication: | Molecular Pharmacology |
| Publisher: | American Society for Pharmacology and Experimental Therapy |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | belinostat; cytochrome P450 3A4; firtecan; glutathione transferase; irinotecan; messenger RNA; multidrug resistance protein 1; pregnane X receptor; rifampicin; steroid receptor coactivator 1; ABCB1 protein, human; belinostat; CYP3A4 protein, human; cytochrome P450 3A; hydroxamic acid; irinotecan; pregnane X receptor; rifampicin; steroid receptor; sulfonamide, Article; cancer resistance; gene expression; human; human cell; liver cell; liver cell carcinoma; LS174T cell line; molecular docking; peripheral T cell lymphoma; priority journal; protein conformation; receptor binding assay; reverse transcription polymerase chain reaction; RNA isolation; adult; drug effect; female; male; metabolism; middle aged; procedures; tumor cell line; young adult, Adult; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Cytochrome P-450 CYP3A; Female; Gene Expression; Hepatocytes; Humans; Hydroxamic Acids; Irinotecan; Male; Middle Aged; Molecular Docking Simulation; Pregnane X Receptor; Receptors, Steroid; Rifampin; Sulfonamides; Young Adult |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
| Date Deposited: | 28 Oct 2022 05:38 |
| Last Modified: | 28 Oct 2022 05:38 |
| URI: | https://eprints.iisc.ac.in/id/eprint/77715 |
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