Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice

Abstract

High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions of the colon, stomach, esophagus, oral cavity, prostate, and breast. Inhibition of FAS with C75 has led to a significant antitumor effect in both human breast and prostate cancer xenografts. Recently, HER2/neu, which has also been identified in preneoplastic breast lesions, has been shown to regulate FAS expression through the PI3K/Akt signal transduction pathway rendering them susceptible to FAS inhibition. Utilizing the neu-N transgenic mouse model of mammary cancer, weekly treatment of the neu-N mice with C75 (30 mg/kg) for 10 weeks significantly delayed tumor progression. Only 20% of the C75-treated transgenic mice developed mammary carcinoma by 220 days, compared to 50% in the vehicle control animals. Two C75-treated animals never developed mammary cancer. Analysis of mammary tissue following 10 weeks of C75 treatment revealed a significant delay in mammary maturation as manifested by a reduction of the number and caliber of mammary ducts and budding epithelial structures. Apoptotic changes were increased, DNA synthesis was decreased, and the expressions of FAS, neu, Akt, phospho-Akt, and p21 waf1 were all decreased when compared to vehicle controls and FVB/N mice. Importantly, these effects were restricted to the breast epithelial cells that overexpressed neu, not involving other normal duct structures in the skin, liver, or kidney. C247, an FAS inhibitor chemically distinct from C75, significantly delayed mammary maturation similar to C75. Thus, pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance of the malignant phenotype. Moreover, these data identify FAS as a potential novel drug target for breast cancer chemoprevention.

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

“…For instance, it has been shown that C75 has anti-tumor activity in xenograft models of breast, 48 lung, 49 prostate 50 and renal 51 cancers, and it prevents breast cancer formation in HER2 transgenic mice. 52 TVB-2640 is the most recent orally available FASN inhibitor. It is currently in phase I clinical trial for the treatment of solid tumors (https://clinical trials.gov/ct2/show/NCT02223247).…”

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

“…7,8,24 Moreover, the inhibition of FASN activity is chemopreventive in the neu-N mouse model for breast cancer. 25 The biological mechanisms responsible for the FASN inhibition-induced apoptosis are still not clear. The extrinsic pathway of apoptosis triggered by death domains was described in breast cancer cells because of the accumulation of malonyl-CoA and ceramide after FASN silencing with siRNA.…”

Emerging Therapies for Esophageal Cancer

“…Antineoplastic activity, without anorectic effects, can be achieved with this drug by selective pharmacologic inhibition of FAS without stimulation of CPT1, and we demonstrated effective treatment of mice bearing xenografts of the Colo680N squamous cell esophageal cancer cell line using this drug (figure4). Other animal experiments have also found C93 to work well for treatment of cancer xenografts in a variety of other tumor types [98,[109][110][111][112], and encouraging results have been seen in cancer chemoprevention experiments [113,114]. …”