Targeting fatty acid synthase to inhibit tumor growth and overcome taxane resistance

Abstract We recently found that a diet composed of 15% of total calories as carbohydrate (CHO), primarily as amylose, 35% soy protein and 50% fat, primarily as fish oil (FO) (15%Amylose/Soy/FO) was highly effective at preventing lung nodule formation in a nicotine-derived nitrosamine ketone (NNK)-induced lung cancer model. We asked herein whether adopting such a diet once cancers are established might also be beneficial. To test this, NNK-induced lung nodules were established in mice on a Western diet and the mice were then either kept on a Western diet or switched to various low CHO diets. Since we previously found that sedentary mice develop more lung nodules than active mice, we also compared the effect of exercise in this cancer progression model. We found that switching to a 15%Amylose/Soy/FO diet reduced lung nodules and slowed tumor growth with both ‘active’ and ‘sedentary’ mice. Ki67, cleaved caspase 3 and Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling assays suggested that the efficacy of the 15%Amylose/Soy/FO in lowering tumor nodule count and size was not due to a reduction in tumor cell proliferation, but to an increase in apoptosis. The 15%Amylose/Soy/FO diet also significantly lowered liver fatty acid synthase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 expression, pointing to a global metabolic switch from glycolysis to fatty acid oxidation. Mice fed the 15%Amylose/Soy/FO diet also had significantly reduced plasma levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor α. These results suggest that the 15%Amylose/Soy/FO diet may slow tumor growth by suppressing proinflammatory cytokines, inducing a metabolic switch away from glycolysis and inducing apoptosis in tumors.

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The fatty acid synthase inhibitor orlistat reduces tumor growth and lymph node metastasis in an orthotopic murine model of oral squamous cell carcinoma

Oral Surgery Oral Medicine Oral Pathology and Oral Radiology ◽

10.1016/j.oooo.2012.08.386 ◽

2012 ◽

Vol 114 (4) ◽

pp. e126-e127

Keyword(s):

Squamous Cell Carcinoma ◽

Lymph Node ◽

Fatty Acid ◽

Lymph Node Metastasis ◽

Oral Squamous Cell Carcinoma ◽

Tumor Growth ◽

Murine Model ◽

Fatty Acid Synthase ◽

Node Metastasis ◽

Synthase Inhibitor

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Effects of orlistat combined with enzalutamide and castration through inhibition of fatty acid synthase in a PC3 tumor-bearing mouse model

Bioscience Reports ◽

10.1042/bsr20204203 ◽

2021 ◽

Author(s):

Yeu-Sheng Tyan ◽

Yen-Po Lee ◽

Hui-Yen Chuang ◽

Wei-Hsun Wang ◽

Jeng-Jong Hwang

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Fatty Acid ◽

Mouse Model ◽

Tumor Growth ◽

Fatty Acid Synthase ◽

Synergistic Effects ◽

Growth Delay ◽

Tumor Bearing Mouse ◽

Tumor Bearing

Androgen deprivation therapy (ADT) is one of the typical treatments used for patients with prostate cancer (PCa). ADT, however, may fail when PCa develops castration-resistance. Fatty acid synthase (FASN), a critical enzyme involved in fatty acid synthesis, is found to be upregulated in PCa. Since enzalutamide and ADT are frequently used for the treatment of PCa, this study aimed to unravel the underlying mechanism of combination of orlistat, a FASN inhibitor, and enzalutamide using PC3 cell line; and orlistat and castration in PC3 tumor-bearing animal model. Cytotoxicity was determined by AlamarBlue assay. Drug effects on the cell cycle and protein expressions were assayed by the flow cytometry and Western blot. Electromobility shift assay was used to evaluate the NF-κB activity. The tumor growth delay, expressions of the signaling–related proteins, and histopathology post treatments of orlistat and castration were evaluated in PC3 tumor-bearing mouse model. The results showed that orlistat arrested the PC3 cells at the G1 phase of the cell cycle and enhanced the cytotoxic effects of enzalutamide synergistically. Pretreatment with orlistat combined with castration inhibited the tumor growth significantly compared with those of castration and orlistat treatments alone in PC3 tumor-bearing mice. Combination treatment reduced both fatty acid synthase and NF-κB activities and their downstream effector proteins. The present study demonstrated the synergistic effects of orlistat combined with enzalutamide in vitro and castration in vivo on human prostate cancer.

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Up-regulation of fatty acid synthase induced by EGFR/ERK activation promotes tumor growth in pancreatic cancer

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2015.05.108 ◽

2015 ◽

Vol 463 (4) ◽

pp. 612-617 ◽

Cited By ~ 40

Author(s):

Yong Bian ◽

Yun Yu ◽

Shanshan Wang ◽

Lin Li

Keyword(s):

Pancreatic Cancer ◽

Fatty Acid ◽

Tumor Growth ◽

Fatty Acid Synthase ◽

Erk Activation

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Second-generation inhibitors of fatty acid synthase for lung cancer treatment

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18185 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18185-18185

Author(s):

H. Orita ◽

J. Coulter ◽

E. Tully ◽

M. Pinn ◽

J. Thupari ◽

...

Keyword(s):

Lung Cancer ◽

Fatty Acid ◽

Tumor Growth ◽

Cancer Treatment ◽

Fatty Acid Oxidation ◽

Fatty Acid Synthase ◽

Second Generation ◽

Acid Oxidation ◽

Lung Cancer Treatment ◽

Stimulation Of

18185 Fatty acid synthase (FAS) is highly expressed in many human cancers, including lung cancers. Previous work has shown that blocking FAS activity by cerulenin, a natural antibiotic, or C75, a first-generation synthetic small molecule, leads to apoptosis in cells that overexpress this enzyme. However, the use of C75 is limited by the dose-dependent anorexia that appears to be associated with stimulation of fatty acid oxidation. Pharmacokinetics studies show that the activity of C75 peaks within hours of administration and by 24 hours, approximately 80% of activity is lost. Thus, the effectiveness of C75 is limited by this short duration of anti-neoplastic activity and the prolonged anorexic effects.Several second-generation novel FAS-inhibitory compounds have been synthesized that show significant inhibition of FAS, without parallel stimulation of fatty acid oxidation. Among the most promising of the compounds is C93, which inhibits FAS at nearly equal potency as C75, but has significantly less stimulation of fatty acid oxidation. We treated mice with xenografts (orthotopic and subcutaneous) developed from 3 different human lung cancer cell lines (H460, A549, and LX-7) with daily intraperitoneal injections of C93 (5 days/week) at 50 mg/kg for 4 weeks and observed significant (up to 70%) inhibition of tumor growth in all xenograft models tested. Furthermore, no significant weight loss and no organ-specific toxicity were recognized in treated animals. These results suggest that it is possible to pharmacologically uncouple inhibition of FAS from stimulation of fatty acid oxidation, and thus achieve anti-neoplastic activity by inhibition of FAS without significant drug-induced anorexia. Finally, we tested an oral formulation of C93 with the intent of developing a dosing protocol suitable for clinical applications. Similar levels of drug in tumor tissue, and similar inhibition of fatty acid synthase enzyme activity, were seen after oral and intraperitoneal administrations of drug. Furthermore, repeated oral administration of C93 to animals with subcutaneous H460 lung cancer xenografts inhibited tumor growth to a similar level observed after intraperitoneal administration. Thus, fatty acid synthase appears to be a promising target for lung cancer treatment. No significant financial relationships to disclose.

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