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Open AccessArticle

Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells

1
IGH, CNRS, University of Montpellier, 34000 Montpellier, France
2
Department of Clinical Hematology, CHU Montpellier, 34395 Montpellier, France
3
Univ Montpellier, UFR de Médecine, 34000 Montpellier, France
4
Univ Montpellier, UMR CNRS 5235, 34000 Montpellier, France
5
Department of Biological Hematology, CHU Montpellier, 34295 Montpellier, France
*
Author to whom correspondence should be addressed.
Current address: Laboratory of Molecular Angiogenesis, GIGA-Cancer, Liege University, 4000 Liege, Belgium.
Cancers 2019, 11(4), 439; https://doi.org/10.3390/cancers11040439
Received: 19 February 2019 / Revised: 15 March 2019 / Accepted: 20 March 2019 / Published: 28 March 2019
(This article belongs to the Special Issue Cancer Chemoresistance)
Background: Multiple myeloma (MM) is the second most common hematological cancer after lymphoma. It is characterized by the accumulation of clonal malignant plasma cells within the bone marrow. The development of drug resistance remains a major problem for effective treatment of MM. Understand the mechanisms underlying drug resistance in MM is a focal point to improve MM treatment. Methods: In the current study, we analyzed further the role of redox imbalance induction in melphalan-induced toxicity both in human myeloma cell lines (HMCLs) and primary myeloma cells from patients. Results: We developed an in-vitro model of short-term resistance to high-dose melphalan and identified that pretreatment with physiological concentration of GSH protects HMCLs from melphalan-induced cell cycle arrest and cytotoxicity. We validated these results using primary MM cells from patients co-cultured with their bone marrow microenvironment. GSH did not affect the ability of melphalan to induce DNA damages in MM cells. Interestingly, melphalan induced reactive oxygen species, a significant decrease in GSH concentration, protein and lipd oxydation together with NRF2 (NF-E2-related factor 2) pathway activation. Conclusions: Our data demonstrate that antioxidant defenses confers resistance to high dose melphalan in MM cells, supporting that redox status in MM cells could be determinant for patients’ response to melphalan. View Full-Text
Keywords: GSH; multiple myeloma; reactive oxygen species; melphalan; drug resistance; NRF2 GSH; multiple myeloma; reactive oxygen species; melphalan; drug resistance; NRF2
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MDPI and ACS Style

Gourzones, C.; Bellanger, C.; Lamure, S.; Gadacha, O.K.; De Paco, E.G.; Vincent, L.; Cartron, G.; Klein, B.; Moreaux, J. Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells. Cancers 2019, 11, 439. https://doi.org/10.3390/cancers11040439

AMA Style

Gourzones C, Bellanger C, Lamure S, Gadacha OK, De Paco EG, Vincent L, Cartron G, Klein B, Moreaux J. Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells. Cancers. 2019; 11(4):439. https://doi.org/10.3390/cancers11040439

Chicago/Turabian Style

Gourzones, Claire; Bellanger, Céline; Lamure, Sylvain; Gadacha, Ouissem K.; De Paco, Elvira G.; Vincent, Laure; Cartron, Guillaume; Klein, Bernard; Moreaux, Jérôme. 2019. "Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells" Cancers 11, no. 4: 439. https://doi.org/10.3390/cancers11040439

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