Targeting unique oxidative metabolism of clonogenic multiple myeloma cells for therapy

Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable despite utilization of aggressive protocols that combine conventional and novel chemotherapy drugs. Recent studies show that drug resistance can be attributable to genetic and developmental heterogeneity in MM. One theory for the high rates of relapse and refractory disease is the existence of a pool of cancer stem cells in MM. We predict that identifying metabolic differences in the MM stem-like cells could offer novel pathways to create combination therapies that would improve the clinical outcome for patients. Utilizing human MM cell lines, we characterized the stem-like population under both normoxic and hypoxic conditions. Our results show that the MM stem-like cells have decreased basal reactive oxygen species (ROS) and increased glucose uptake. Additionally, growth under hypoxia increases the stem-like population and the expression of microRNA-210, a master regulator of hypoxia. Notably, decreasing miR-210 expression alters the rate of cellular metabolism under hypoxia. By combining therapies that increase mitochondrial ROS levels and inhibit glucose metabolism, we attained clonogenic death of MM cells under normoxic conditions. Our studies provide the rationale to further investigate drug combinations that disrupt cellular redox homeostasis to cause oxidative stress-induced cell death to improve therapies for MM patients.