Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts.
A biologically aggressive subset of human breast cancers and other malignancies is characterized by elevated fatty-acid synthase (FAS) enzyme expression, elevated fatty acid (FA) synthesis, and selective sensitivity to pharmacological inhibition of FAS activity by cerulenin or the novel compound C75. In this study, inhibition of FA synthesis at the physiologically regulated step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2-furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays. FAS inhibitors induced a rapid increase in intracellular malonyl-CoA to several fold above control levels, whereas TOFA reduced intracellular malonyl-CoA by 60%. Simultaneous exposure of breast cancer cells to TOFA and an FAS inhibitor resulted in significantly reduced cytotoxicity and apoptosis. Subcutaneous xenografts of MCF7 breast cancer cells in nude mice treated with C75 showed FA synthesis inhibition, apoptosis, and inhibition of tumor growth to less than 1/8 of control volumes, without comparable toxicity in normal tissues. The data suggest that differences in intermediary metabolism render tumor cells susceptible to toxic fluxes in malonyl-CoA, both in vitro and in vivo.
Pizer
E S
ES
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Thupari
J
J
Han
W F
WF
Pinn
M L
ML
Chrest
F J
FJ
Frehywot
G L
GL
Townsend
C A
CA
Kuhajda
F P
FP
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000627:therapeutic use / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000627:therapeutic use / Q000633:toxicity; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008316:Malonyl Coenzyme A / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005663:Furans; D000960:Hypolipidemic Agents; D002569:Cerulenin; D008316:Malonyl Coenzyme A; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; D064429:Fatty Acid Synthases