Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells

Abstract

Abstract. The lipogenic enzyme fatty acid synthase (FASN) is differentially overexpressed and hyperactivated in a biologically aggressive subset of breast carcinomas and minimally in most normal adult tissues, rendering it an interesting target for anti-neoplastic therapy development. We previously reported that the FASN blockade can induce a synergistic chemosensitization of breast cancer cells to microtubule interfering agents (MIAs) such as docetaxel, paclitaxel and vinorelbine. Upon pharmacological inhibition of FASN activity using the natural antibiotic cerulenin [(2S,3R)-2,3-epoxy-4-oxo-7E,10E-dodecadienamide], we evaluated the role of FASN-catalyzed endogenous fatty acid biogenesis on the sensitivity of SK-Br3, MCF-7 and MDA-MB-231 breast cancer cell lines to the anti-metabolite 5-fluorouracil (5-FU). Cells were exposed simultaneously to cerulenin and 5-FU, sequentially to 5-FU followed by cerulenin or cerulenin followed by 5-FU. Cell viability was determined by MTT assays and the increase in 5-FU-induced cell growth inhibition was measured by dividing 5-FU IC 30 and IC 50 values (i.e., 30% and 50% inhibitory concentrations, respectively) that were obtained in the absence of cerulenin by those in its presence. Co-exposure to cerulenin enhanced 5-FU efficacy up to 20-, 81-, and 58-times in SK-Br3, MCF-7 and MDA-MB-231 cells, respectively. Pre-treatment with cerulenin followed by the addition of 5-FU increased 5-FU efficacy up to 31-, 87-, and 126-times in SK-Br3, MCF-7 and MDA-MB-231 cells, respectively. Pre-treatment with 5-FU followed by the addition of cerulenin augmented 5-FU efficacy up to 107-, 20-, and 18-times in SK-Br3, MCF-7 and MDA-MB-231 cells, respectively. When isobologram transformations of multiple dose-response analyses were performed to detect in vitro synergy, we concluded that the nature of the interaction between cerulenin and 5-FU in individual breast cancer cells lines generally exhibited sequence-dependency. Thus, while synergism was mainly observed when breast cancer cells were exposed to 5-FU prior to cerulenin, moderate synergism or additive interactions was obtained either when the chemical FASN blocker preceded 5-FU or when both drugs were concurrently administered. Of note, no antagonist interactions occurred upon any schedule of combined treatment with cerulenin and 5-FU. Our current findings revealing a schedule-dependent synergistic interaction between 5-FU and cerulenin represents, to the best of our knowledge, the first evidence that FASN-catalyzed de novo FA biogenesis plays a key role in regulating breast cancer cell response to antimetabolite-based therapies.

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

“…FASN inhibition has also been described as a sensitizer for cisplatin treatment in mice xenografted with human ovarian cancer cells (30). In fact, FASN is highly expressed across a wide range of human tumor types where its inhibition either induces apoptosis and/or synergizes with cytotoxic agents (31)(32)(33)(34)(35)(36)(37)(38). Consistent with these data, we show that inhibition of FASN with short hairpin RNAs also sensitized our CDH1-deficient cells to cisplatin treatment.…”

Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance

“…Combination of trastuzumab (monoclonal antibody against HER2) and FAS inhibitor results in re-sensitization with trastuzumab in the trastuzumab-resistant breast cancer cells (18). Synergistic therapeutic effect is observed after combination of FAS inhibitors and other chemotherapies (19,20). Therefore, blockage of lipid metabolic enzymes might be a novel strategy for breast cancer treatment.…”

AMPK in Health and Disease

“…FAS is highly expressed in breast cancer and many common human carcinomas. Indeed, FAS is now regarded as an important anticancer drug target (330,515). Inhibition of earlier steps in fatty acid synthesis such the AMPK substrate ACC by the macrocyclic polyketide inhibitor soraphen A has been shown to inhibit proliferation of prostate cancer cells (38).…”