PUBLICATION
The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor
- Authors
- Creusot, N., Gassiot, M., Alaterre, E., Chiavarina, B., Grimaldi, M., Boulahtouf, A., Toporova, L., Gerbal-Chaloin, S., Daujat-Chavanieu, M., Matheux, A., Rahmani, R., Gongora, C., Evrard, A., Pourquier, P., Balaguer, P.
- ID
- ZDB-PUB-200712-1
- Date
- 2020
- Source
- Cells 9(7): (Journal)
- Registered Authors
- Keywords
- colon and liver cancer cells, dabrafenib, hPXR, proliferation
- MeSH Terms
-
- Antineoplastic Agents/pharmacology*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- HeLa Cells
- Hep G2 Cells
- Humans
- Imidazoles/pharmacology*
- Oximes/pharmacology*
- Pregnane X Receptor/metabolism*
- Protein Binding/drug effects
- PubMed
- 32650447 Full text @ Cells
Citation
Creusot, N., Gassiot, M., Alaterre, E., Chiavarina, B., Grimaldi, M., Boulahtouf, A., Toporova, L., Gerbal-Chaloin, S., Daujat-Chavanieu, M., Matheux, A., Rahmani, R., Gongora, C., Evrard, A., Pourquier, P., Balaguer, P. (2020) The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 9(7):.
Abstract
The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous compounds and plays a critical role in the control of detoxifying enzymes and transporters regulating liver and gastrointestinal drug metabolism and clearance. hPXR is also involved in both the development of multidrug resistance and enhanced cancer cells aggressiveness. Moreover, its unintentional activation by pharmaceutical drugs can mediate drug-drug interactions and cause severe adverse events. In that context, the potential of the anticancer BRAF inhibitor dabrafenib suspected to activate hPXR and the human constitutive androstane receptor (hCAR) has not been thoroughly investigated yet. Using different reporter cellular assays, we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813, whereas it does not activate mouse or zebrafish PXR nor hCAR. We also showed that dabrafenib binds to recombinant hPXR, induces the expression of hPXR responsive genes in colon LS174T-hPXR cancer cells and human hepatocytes and finally increases the proliferation in LS174T-hPXR cells. Our study reveals that by using a panel of different cellular techniques it is possible to improve the assessment of hPXR agonist activity for new developed drugs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping