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

  • Authors:
    • Alejando Vazquez-Martin
    • Santiago Ropero
    • Joan Brunet
    • Ramon Colomer
    • Javier A. Menendez
  • View Affiliations

  • Published online on: October 1, 2007     https://doi.org/10.3892/or.18.4.973
  • Pages: 973-980
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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 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.

Related Articles

Journal Cover

October 2007
Volume 18 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Vazquez-Martin A, Ropero S, Brunet J, Colomer R and Menendez JA: Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. Oncol Rep 18: 973-980, 2007
APA
Vazquez-Martin, A., Ropero, S., Brunet, J., Colomer, R., & Menendez, J.A. (2007). Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. Oncology Reports, 18, 973-980. https://doi.org/10.3892/or.18.4.973
MLA
Vazquez-Martin, A., Ropero, S., Brunet, J., Colomer, R., Menendez, J. A."Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells". Oncology Reports 18.4 (2007): 973-980.
Chicago
Vazquez-Martin, A., Ropero, S., Brunet, J., Colomer, R., Menendez, J. A."Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells". Oncology Reports 18, no. 4 (2007): 973-980. https://doi.org/10.3892/or.18.4.973