Abstract
Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40–70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.
Highlights
Oncogenic transformation of normal cells into tumor cells involves a well-orchestrated metabolic reprogramming of glucose and fatty acid metabolism
We first characterized the fatty acid oxidation and de novo fatty acid synthesis capacity in three human myeloma cell lines (RPMI-8226, NCI-H929 and U-266B1); and second, we investigated the sensitivity of myeloma cells to fatty acid oxidation and de novo fatty acid synthesis inhibition
A specific and irreversible inhibitor of carnitine palmitoyl transferase (CPT) I, is a clinically well-tolerated drug that has been used in clinical trials in patients with chronic heart failure and diabetes [11,12,17,18]
Summary
Oncogenic transformation of normal cells into tumor cells involves a well-orchestrated metabolic reprogramming of glucose and fatty acid metabolism. Glucose is consumed at a high rate to produce lactate and ATP even in the presence of oxygen. This metabolic adaptation from oxidative to glycolytic metabolism, known as the ‘‘Warburg effect’’, was first reported by Otto Warburg in the 1920s [2,3]. At first glance, these metabolic alterations in glucose metabolism seems to be inappropriate to sustain tumor cells growth and survival, because aerobic glycolysis is 18-fold less efficient to produce ATP than oxidative phosphorylation. Tumor cells overcome this limitation increasing the glycolytic flux of glucose by a mechanism that at least involves upregulation of glucose transporter 1 (GLUT1) [4]
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