orlistat and etomoxir

Prostate cancer is the most commonly diagnosed malignancy among Western men and accounts for the second leading cause of cancer-related deaths. Prostate cancer tends to grow slowly and recent studies suggest that it relies on lipid fuel more than on aerobic glycolysis. However, the biochemical mechanisms governing the relationships between lipid synthesis, lipid utilization, and cancer growth remain unknown. To address the role of lipid metabolism in prostate cancer, we have used etomoxir and orlistat, clinically safe drugs that block lipid oxidation and lipid synthesis/lipolysis, respectively. Etomoxir is an irreversible inhibitor of the carnitine palmitoyltransferase (CPT1) enzyme that decreases β oxidation in the mitochondria. Combinatorial treatments using etomoxir and orlistat resulted in synergistic decreased viability in LNCaP, VCaP, and patient-derived benign and prostate cancer cells. These effects were associated with decreased androgen receptor expression, decreased mTOR signaling, and increased caspase-3 activation. Knockdown of CPT1A enzyme in LNCaP cells resulted in decreased palmitate oxidation but increased sensitivity to etomoxir, with inactivation of AKT kinase and activation of caspase-3. Systemic treatment with etomoxir in nude mice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease prostate cancer tumor growth.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carnitine O-Palmitoyltransferase; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Enzyme Inhibitors; Epoxy Compounds; Humans; Hypoglycemic Agents; Lactones; Lipid Metabolism; Male; Metabolism; Mice; Mice, Nude; Orlistat; Oxidation-Reduction; Prostatic Neoplasms; Random Allocation; Signal Transduction; Xenograft Model Antitumor Assays

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.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Boronic Acids; Bortezomib; Carbohydrate Metabolism; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cerulenin; Cyclin-Dependent Kinase Inhibitor p21; Drug Synergism; Epoxy Compounds; Fatty Acids; G1 Phase Cell Cycle Checkpoints; Glucose; Humans; Lactones; Lipid Metabolism; Multiple Myeloma; Orlistat; Oxidation-Reduction; Pyrazines; Retinoblastoma Protein