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[Cancer Research 60, 213-218, January 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Malonyl-Coenzyme-A Is a Potential Mediator of Cytotoxicity Induced by Fatty-Acid Synthase Inhibition in Human Breast Cancer Cells and Xenografts1

Ellen S. Pizer, Jagan Thupari, Wan Fang Han, Michael L. Pinn, Francis J. Chrest, Gojeb L. Frehywot, Craig A. Townsend and Francis P. Kuhajda2

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224 [E. S. P., J. T., W. F. H., M. L. P., F. P. K.]; Research Resources Branch/Flow Cytometry Unit, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224 [F. J. C.]; and Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218 [G. L. F., C. A. T.]

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.




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