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

Oncol Rep. 2007 Oct;18(4):973-80.


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 IC30 and IC50 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cell Survival / drug effects*
  • Cerulenin / pharmacology*
  • Drug Interactions
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Fatty Acid Synthase, Type I / antagonists & inhibitors*
  • Fatty Acid Synthase, Type I / metabolism
  • Fluorouracil / pharmacology*
  • Humans
  • Tumor Cells, Cultured / drug effects


  • Cerulenin
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Fluorouracil