TY - JOUR
T1 - Drug metabolism and clearance system in tumor cells of patients with multiple myeloma
AU - Hassen, Wafa
AU - Kassambara, Alboukadel
AU - Reme, Thierry
AU - Sahota, Surinder
AU - Seckinger, Anja
AU - Vincent, Laure
AU - Cartron, Guillaume
AU - Moreaux, Jérôme
AU - Hose, Dirk
AU - Klein, Bernard
PY - 2015
Y1 - 2015
N2 - 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 Multiple Myeloma, Drug Metabolism and Clearance, Prognosismajority 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 (RXRa, 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 RXRa, PXR, LXR and FXR through agonists could open new perspectives to alleviate or reverse MM drug resistance.
AB - 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 Multiple Myeloma, Drug Metabolism and Clearance, Prognosismajority 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 (RXRa, 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 RXRa, PXR, LXR and FXR through agonists could open new perspectives to alleviate or reverse MM drug resistance.
KW - Drug metabolism and clearance
KW - Multiple myeloma
KW - Prognosis
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U2 - 10.18632/oncotarget.3237
DO - 10.18632/oncotarget.3237
M3 - Article
C2 - 25669983
AN - SCOPUS:84925649577
SN - 1949-2553
VL - 6
SP - 6431
EP - 6447
JO - Oncotarget
JF - Oncotarget
IS - 8
ER -