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

Claire Gourzones,Guillaume Cartron,Elvira De Paco,Bernard Klein,Laure Vincent,Sylvain Lamure,Jérôme Moreaux,Céline Bellanger,Ouissem Gadacha

doi:10.3390/cancers11040439

Abstract

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.

Highlights

Multiple myeloma (MM) is a malignant plasma cell disorder affecting approximately 70,000 new patients/year around the world
To determine the range of melphalan concentrations inducing MM cell death and the differences of sensitivity between cell lines, dose response-curves were performed using seven human myeloma cell lines (HMCLs) representative of the molecular heterogeneity encountered in MM patients [23] (Figure 1A)
In order to define a role of reactive oxygen species (ROS) induction in melphalan-induced cytoxicity, MM cells were treated by melphalan alone or in combination with various antioxidants (Figure 1B,C)

Summary

Introduction

Multiple myeloma (MM) is a malignant plasma cell disorder affecting approximately 70,000 new patients/year around the world. Treatment of this disease is regularly improving with the development of new drugs and the design of better combinations [1]. 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.

Methods

Results

Discussion

Conclusion