Inhibition of tumor-associated fatty acid synthase activity enhances vinorelbine (Navelbine)-induced cytotoxicity and apoptotic cell death in human breast cancer cells.
The lipogenic enzyme fatty acid synthase (FAS) 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. Current trends in the treatment of human breast cancer are with drug combinations that result in improved responses as well as the ability to use less toxic concentrations of the drugs. Here, we envisioned that combinations of conventional chemotherapeutic agents with novel compounds directed against breast cancer-associated FAS hyperactivity may provide increased efficacy over existing therapy for human breast cancer. Specifically, we examined the ability of the mycotoxin cerulenin, a potent and non-competitive inhibitor of FAS activity, to enhance the cytotoxic effects of vinorelbine (Navelbine), a derivative of vinca alkaloid that interferes with tubulin assembly and exhibits activity against metastatic breast cancer. SK-Br3, MCF-7 and MDA-MB-231 human breast cancer cell lines were employed as models of high, moderate and low levels of FAS ('cerulenin-target'), respectively. Combinations of cerulenin with vinorelbine were tested for synergism, additivity or antagonism using the isobologram and the median-effect plot (Chou-Talalay) analyses. Breast cancer cells were either simultaneously exposed to cerulenin and vinorelbine for 24 h or sequentially to cerulenin for 24 h followed by vinorelbine for 24 h. Concurrent exposure to cerulenin and vinorelbine resulted in synergistic interactions in MCF-7 and MDA-MB-231 cell lines, while additivity was found in SK-Br3 cells. Sequencing cerulenin followed by vinorelbine resulted in synergism for SK-Br3 and MDA-MB-231 cells, whereas it showed additive effects in MCF-7 cells. FAS activity blockade was found to synergistically enhance apoptosis-inducing activity of vinorelbine, as determined by an enzyme-linked immunosorbent assay for histone-associated DNA fragments. To the best of our knowledge this is the first study demonstrating that breast cancer-associated FAS is playing an active role in human breast cancer chemosensitivity. We suggest that pharmacological inhibition of FAS activity is a novel molecular approach to enhance the cytotoxic effects of existing chemotherapeutic agents in human breast cancer.
Menendez
Javier A
JA
Department of Medicine, Evanston Northwestern Research Institute, Evanston, IL 60201, USA.
Colomer
Ramon
R
Lupu
Ruth
R
D000935:Antifungal Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002569:Cerulenin / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D020128:Inhibitory Concentration 50; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077235:Vinorelbine
D000935:Antifungal Agents; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D002569:Cerulenin; D014747:Vinblastine; D004247:DNA; D064429:Fatty Acid Synthases; C022616:thiazolyl blue; D000077235:Vinorelbine