Multiple myeloma (MM) is an incurable plasma cell malignancy. Human MM cell lines and primary patient samples have a glycolytic phenotype, which has been studied as a potential treatment target. Dichloroacetate (DCA) is a pyruvate dehydrogenase (PDH) kinase (PDK) inhibitor that can reverse the glycolytic phenotype, decreasing pPDH and reducing lactate production by redirecting pyruvate flux into the mitochondria. Studies showed DCA inhibited MM cell proliferation and induced apoptosis (1, 2). Glucocorticoids such as dexamethasone (DEX) are standard treatment in MM, however drug resistance is common. An increased glycolytic ratio was associated with glucocorticoid resistance, which was overcome by reversing the glycolytic phenotype (3).
We hypothesized that DCA can inhibit MM cell growth and increase sensitivity to DEX by altering the glycolytic phenotype.
The response of five human MM cell lines to DCA (1,3,5mM) for 72 hours was measured using neutral red uptake assay. DCA alone reduced total viable cell number in 4/5 cell lines (38% (RPMI 8226), 25% (NCI-H929), 42% (MM.1S) and 13% (MM.1R) reduction; no response in U266). Trypan blue exclusion, proliferation and apoptosis assays demonstrated that DCA decreased cell proliferation without increasing apoptosis. DCA decreased pPDH in responsive cell lines. The 4 PDK targets vary in sensitivity to DCA, with PDK3 being the least sensitive. PDKs profiles were screened by western blotting, and found that MM.1R expressed higher levels of PDK3 compared to MM.1S, which may explain its relative insensitivity to DCA. DCA and DEX co-treatment reduced the EC50 for DEX 10-fold in both DEX sensitive (MM.1S: from ~0.01μM to ~0.001μM) and DEX resistant (MM.1R: from ~100 μM to ~10 μM) cell lines.
Thus DCA may be a useful addition to standard MM therapies. We are currently investigating this in a clinical trial at The Canberra Hospital.