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

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.

XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

“…In contrast, RPMI8226 and U266 exhibited considerable resistance to melphalan in comparison with H929 and MM1S in our experimental setting, as evidenced by increased IC 50 values (10.0 ± 1.5 and 14.8 ± 1.8 µM for RPMI8226 and U266, respectively). This observation is consistent with previous studies showing that MM1S and H929 appear to be more sensitive to melphalan than RPMI8226 and U266 . Notably, while MM1S and H929 harbor TP53 wild‐type (WT) gene, there are missense mutations in TP53 in RPMI8226 and U266, which lead to P53 E285K and A161T mutant proteins, respectively .…”

“…Melphalan-induced DNA repair in MM cell lines In contrast, RPMI8226 and U266 exhibited considerable resistance to melphalan in comparison with H929 and MM1S in our experimental setting, as evidenced by increased IC 50 values (10.0 ± 1.5 and 14.8 ± 1.8 µM for RPMI8226and U266, respectively). This observation is consistent with previous studies showing that MM1S and H929 appear to be more sensitive to melphalan than RPMI8226 and U266 [29][30][31][32]. Notably, while MM1S and…”

ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance

“…Current MM treatments involves proteasome inhibitors, immunomodulators, an alkylating agent melphalan, and high-dose dexamethasone [1]. Gourzones et al reported that melphalan induces ROS and antioxidants involved in glutathione synthesis and regeneration protect cells from melphalan-induced cell death [40]. However, other antioxidant drugs have no effect on melphalan-mediated toxicity while protecting cells from BTZ.…”

Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From “Omics” Research

“…Recently, it was demonstrated that the cytotoxicity on MM cells of melphalan, a central chemotherapeutic in MM treatment, is partly mediated by the generation of oxidative stress and can be antagonized by antioxidant mechanisms. Glutathione, a physiological antioxidant agent, could reduce melphalan-induced apoptosis and cell cycle alterations but this effect was independent from melphalan-induced DNA damage (32).…”