Combined Valproic Acid, Bezafibrate, and Medroxyprogesterone Acetate Inhibit Proliferation and Induce Death of Multiple Myeloma Cells in MSC Conditioned Medium

Background: Multiple myeloma is a B-cell malignancy that typically affects the elderly. The standard treatment relies on autosomal stem cell transplant with high-dose chemotherapy, which is not possible in most cases due to age and other comorbidities. Several novel therapies have been demonstrated to have improved the outcome; however, combination therapies are still required due to toxicity associated with high doses of individual drugs, which makes the treatment very expensive, yet not curable. This study aims to evaluate the efficacy of widely available and affordable redeployed drugs valproic acid, bezafibrate, and medroxyprogesterone acetate against P3U1 multiple myeloma cells. Methods: ST2 mouse bone marrow-derived mesenchymal stromal cell (BM-MSC) derived conditioned medium was used to mimic the bone marrow microenvironment, which facilitates myeloma cell growth. Different combinations of valproic acid, bezafibrate, and medroxyprogesterone acetate were tested against P3U1 mouse myeloma cells in terms of cell proliferation by colorimetric MTS assay, viability percentage by LIVE/DEAD staining, and induction of intracellular reactive oxygen species (ROS) in both the control medium and the conditioned medium. Results: In the control medium, valproic acid alone enhanced P3U1 myeloma cell proliferation on MTS assay but induced cell death observed in LIVE/DEAD assay. The combination of bezafibrate and medroxyprogesterone acetate (denoted BaP) inhibited cell proliferation and increased cell death in a dose-dependent manner. Adding valproic acid to Bap (denoted VBaP) further increased the efficacy in BaP concentration-dependent manner. Reactive oxygen species (ROS) were detected following VBaP treatment, suggestive of oxidative stress-mediated cell killing. In ST2 BM-MSC derived conditioned medium, VBaP significantly reduced P3U1 cell proliferation and enhanced P3U1 cell death at a clinically achievable dose. Conclusion: VBaP combination is an exciting prospect in developing an affordable and readily available novel drug treatment for multiple myeloma, particularly in the context of the bone marrow microenvironment in which these malignant cells prosper.