Oncotarget

Clinical Research Papers:

Drug metabolism and clearance system in tumor cells of patients with multiple myeloma

Wafa Hassen, Alboukadel Kassambara, Thierry Reme, Surinder Sahota, Anja Seckinger, Laure Vincent, Guillaume Cartron, Jérôme Moreaux, Dirk Hose and Bernard Klein _

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Oncotarget. 2015; 6:6431-6447. https://doi.org/10.18632/oncotarget.3237

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Abstract

Wafa Hassen1,2, Alboukadel Kassambara1,3, Thierry Reme1,3, Surinder Sahota4, Anja Seckinger5,6, Laure Vincent7, Guillaume Cartron7, Jérôme Moreaux1,3,8, Dirk Hose5,6 and Bernard Klein1,3,8

1 Institute of Human Genetics, CNRS-UPR1142, Montpellier, France

2 High Institute of Biotechnology of Monastir, University of Monastir, Tunisia

3 CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biological Haematology, Montpellier, France

4 Cancer Sciences Unit, Faculty of Medicine, University of Southampton, UK

5 Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany

6 Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany

7 CHU Montpellier, Department of Clinical Hematology, Montpellier,  France

8 University of Montpellier 1, UFR Medicine, Montpellier, France

Correspondence:

Bernard Klein, email:

Keywords: Multiple Myeloma, Drug Metabolism and Clearance, Prognosis

Received: October 21, 2014 Accepted: December 10, 2014 Published: December 26, 2014

Abstract

Resistance to chemotherapy is a major limitation of cancer treatments with several molecular mechanisms involved, in particular altered local drug metabolism and detoxification process. The role of drug metabolism and clearance system has not been satisfactorily investigated in Multiple Myeloma (MM), a malignant plasma cell cancer for which a majority of patients escapes treatment. The expression of 350 genes encoding for uptake carriers, xenobiotic receptors, phase I and II Drug Metabolizing Enzymes (DMEs) and efflux transporters was interrogated in MM cells (MMCs) of newly-diagnosed patients in relation to their event free survival. MMCs of patients with a favourable outcome have an increased expression of genes coding for xenobiotic receptors (RXRα, LXR, CAR and FXR) and accordingly of their gene targets, influx transporters and phase I/II DMEs. On the contrary, MMCs of patients with unfavourable outcome displayed a global down regulation of genes coding for xenobiotic receptors and the downstream detoxification genes but had a high expression of genes coding for ARNT and Nrf2 pathways and ABC transporters. Altogether, these data suggests ARNT and Nrf2 pathways could be involved in MM primary resistance and that targeting RXRα, PXR, LXR and FXR through agonists could open new perspectives to alleviate or reverse MM drug resistance.


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