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.