Inhibition Of Fatty Acid Synthase Activity Research Articles

Fatty Acid Synthase Inhibitory Activity of Euphorbia peplus and its Secondary Metabolites

Fatty Acid Synthase Inhibitory Activity of Euphorbia peplus and its Secondary Metabolites

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells.

Lipid metabolic reprogramming is an emerging characteristic of endocrine therapy (ET) resistance in estrogen receptor-positive (ER+) breast cancer. We explored changes in lipid metabolism in ER+ breast cancer cell lines following acquired resistance to common endocrine treatments and tested efficacy of an inhibitor in current clinical trials. We derived ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD). Parental and ET resistant cells were subjected to global gene expression and unbiased lipidomic profiling. Lipid storage changes were assessed via neutral lipid staining with Oil Red O (ORO). The impact of the fatty acid synthase (FASN) inhibitor TVB-2640 on the growth and lipid storage of these cell lines was evaluated. Additionally, 13 C 2 -acetate tracing was used to examine FASN activity in parental and ET resistant cells in the absence or presence of TVB-2640. Compared to parental cells, lipid metabolism and processing pathways were notably enriched in ET resistant cells, which exhibited distinct lipidomes characterized by increased triglyceride and polyunsaturated FA (PUFA) species. ET-resistant cells displayed enhanced cytoplasmic lipid droplets. Increased FASN protein levels were observed in ET-resistant cells, and TVB-2640 effectively inhibited FASN activity. FASN inhibition reduced cell growth in some but not all cell lines and ET resistance types and did not correlate to lipid storage reduction. 13 C 2 -acetate tracing confirmed reduced palmitate synthesis and enhanced PUFA synthesis in ET-resistant cells, especially when combined with FulvR. ET resistant breast cancer cells exhibit a shift towards enhanced triglyceride storage and complex lipids enriched with PUFA acyl chains. While targeting FASN alongside ET may not fully overcome ET resistance in our models, focusing on the unique lipid metabolic dependencies, such as PUFA pathways, may present a promising alternative strategy for treating ET resistant breast cancer.

High-intensity interval training induces lactylation of fatty acid synthase to inhibit lipid synthesis

BackgroundThe aim of study was to observe the effect of increased lactate levels during high-intensity interval training (HIIT) on protein lactylation, identify the target protein, and investigate the regulatory effect of lactylation on the function of the protein.MethodsC57B/L6 mice were divided into 3 groups: the control group, HIIT group, and dichloroacetate injection + HIIT group (DCA + HIIT). The HIIT and DCA + HIIT groups underwent 8 weeks of HIIT treatment, and the DCA + HIIT group was injected DCA before HIIT treatment. The expression of lipid metabolism-related genes was determined. Protein lactylation in subcutaneous adipose tissue was identified and analyzed using 4D label-free lactylation quantitative proteomics and bioinformatics analyses. The fatty acid synthase (FASN) lactylation and activity was determined.ResultsHIIT had a significant effect on fat loss; this effect was weakened when lactate production was inhibited. HIIT significantly upregulated the protein lactylation while lactate inhibition downregulated in iWAT. FASN had the most modification sites. Lactate treatment increased FASN lactylation levels, inhibited FASN activity, and reduced palmitate and triglyceride synthesis in 3T3-L1 cells.ConclusionsThis investigation revealed that lactate produced by HIIT increased protein pan-lactylation levels in iWAT. FASN lactylation inhibited de novo lipogenesis, which may be an important mechanism in HIIT-induced fat loss.

α-Mangostin suppresses proliferation and invasion in osteosarcoma cells via inhibiting fatty acid synthase

• α-mangostin was able to induce human osteosarcoma cells apoptosis via downregulating fatty acid synthase (FASN) expression in dose-dependent manner. • α-mangostin, as a FASN inhibitor, plays a great role in regulated ER stress-related protein and signal protein expression. • α-mangostin induced FASN inhibition, which might influence osteosarcoma progression, invasion and migration. Fatty acid synthase (FASN) is highly expressed in multiple types of human cancers and is recognized as one of the therapeutic targets for treating cancer metastasis. α-Mangostin is a natural xanthone extracted from mangosteen fruit, and possesses various biological activities. In our previous studies, α-mangostin was found to inhibit FASN activity. The present study was designed to reveal the effects of α-mangostin on osteosarcoma and to reveal whether the mechanism of α-mangostin in anticancer activity is related to FASN inhibition. Cytotoxicity was assessed in osteosarcoma MG63, 143B and U2OS cells. Cell viability was detected by an MTT assay. The protein expression levels were detected by western blotting. Flow cytometry, Annexin V/propidium iodide dual staining and Hoechst 33258 staining were performed to assess the apoptotic effects. Wound healing and Transwell assays were used to detect the inhibitory effect of α-mangostin on osteosarcoma cells invasion and migration. We found that α-mangostin blocked FASN expression, inhibited osteosarcoma cell proliferation, invasion and migration in a dose-dependent manner. In addition, α-mangostin regulated endoplasmic reticulum transmembrane receptors and signal protein expression in osteosarcoma cells. These findings suggested that α-mangostin suppresses osteosarcoma cell proliferation and metastasis by inhibiting FASN expression, which provides a basis as a potential target for osteosarcoma treatment.

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation

BackgroundPhosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC.MethodsCorrelation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism.ResultsCorrelation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo.ConclusionsDownregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

Triclosan down-regulates fatty acid synthase through microRNAs in HepG2 cells

Triclosan is a promising candidate of fatty acid synthase (FASN) inhibitor by blocking FASN activity, but its effect on FASN expression and the underling epigenetic mechanism remain elusive. In this study, the effect of triclosan on FASN mRNA and protein expressions in human HepG2 cells and the regulatory role of microRNAs (miRNAs) in the downregulation of FASN induced by triclosan were explored through experiments and bioinformatics analysis. The results showed that triclosan not only directly inhibited FASN activity, but also significantly decreased FASN mRNA and protein levels in human liver HepG2 cells. Nine miRNAs targeting FASN mRNA degradation were identified by miRNA prediction tools, and the expression levels of these nine miRNAs were then detected by real-time quantitative PCR. Triclosan significantly increased the expressions of the six miRNAs, namely miR-15a, miR-107, miR-195, miR-424, miR-497 and miR-503, leading to the downregulation of FASN. Further investigation revealed that the six triclosan-upregulated miRNAs played an important regulatory role in lipid metabolism and cell cycle by gene ontology annotations and pathway analysis. Consistent with the results of bioinformatics analyses, triclosan significantly reduced the intracellular lipid content by triglyceride assay, oil red O, BODIPY 493/503 and Nile Red staining, thereby inhibiting the growth of HepG2 cells through apoptosis. Taken together, our study reveals that triclosan downregulates FASN expression through a variety of miRNAs, providing new insight for triclosan as a FASN inhibitor candidate to regulate lipid metabolism in human hepatoma cells.

Inhibiting fatty acid synthase in operable triple negative breast cancer.

584 Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had >cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .

Abstract OT1-03-01: Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy

Abstract Background Human Fatty Acid Synthase (FASN) is the sole cytosolic enzyme responsible for de novo synthesis of long chain fatty acids. Unlike normal tissues, cancer cells require FASN dependent fatty acid synthesis for survival. FASN is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and associated with significantly shorter disease free and overall survival. In vitro, FASN overexpression induces resistance to multiple DNA damaging agents including doxorubicin and cisplatin. Proton pump inhibitors (PPI), particularly omeprazole can selectively inhibit FASN enzyme activity at a Ki of 3.4umol. Inhibition of FASN activity with PPIs induces apoptosis selectively in cancer cells with minimal effect on non-malignant breast cell lines. PPIs are well tolerated and are FDA approved for a variety of gastro-intestinal disorders. We hypothesize that PPIs will effectively inhibit FASN activity and improve clinical efficacy of neoadjuvant chemotherapy with minimal added toxicity in operable TNBC. Materials and Methods This is a single arm multi -center phase II study of omeprazole 80mg PO BID in combination with standard neoadjuvant anthracycline-weekly taxane chemotherapy (AC-T; Adriamycin 60mg/m2 Cyclophosphamide 600mg/m2 given every q2w with G-CSF or q 3wk x 4 followed by weekly paclitaxel 80mg/m2 x 12) in patients with newly diagnosed clinically stage II or greater TNBC (NCT02595372). Neoadjuvant carboplatin may be offered with weekly paclitaxel at treating physician’s discretion. Patients with prior over the counter or prescription PPI use within 12 months are excluded. An initial core biopsy is performed at baseline, after which patients begin omeprazole monotherapy for a brief period (4-7 days). This is followed by a second research core biopsy and initiation of standard AC-T. PPI is continued until night before definitive surgery. Study follow up ends with definitive surgery and after resolution of known adverse events (<=G1). The primary endpoint is the rate of pCR (defined as no residual invasive disease in breast or axilla) in study patients with FASN expression. Relevant secondary endpoints include rate of pCR in all patients, change in FASN expression, enzymatic activity and downstream target gene expression from baseline to surgery; safety and limited omeprazole PK sampling during the study. Assuming that 70% of newly diagnosed TNBC have FASN expression, a single stage phase II trial to detect a pCR rate of 60% (null= pCR-40%) with 80% power and alpha of 0.10 requires 30 FASN patients (or 42 patients total). This sample size also provides approximately 80% power to identify a change in FASN expression and/or activity of 0.5 SDs using a paired t-test and significance level of 0.05. Conclusion The study enrolled its last participant in May 2019. Six patients are in follow-up who have yet to undergo definitive surgery. Final study patient is anticipated to have surgery in October 2019, with final data analysis planned in the last quarter of 2019. Funding This work has been supported by the Breast Cancer Research Foundation. Citation Format: Sagar Sardesai, Alexandra Thomas, Christopher Gallagher, Filipa Lynce, Yvonne Ottaviano, Tarah Ballinger, Brian P Schneider, Anna Maria Storniolo, Susan Perkins, Jian Tian Zhang, Kathy D Miller. Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-01.

COMPARISON OF THE EFFECTS OF DIFFERENT FATTY ACID SYNTHASE INHIBITORS ON THE CELL CYCLE, APOPTOSIS, AND MORPHOLOGY OF SQUAMOUS CELL CARCINOMA 9 CELLS

The aim of this study was to compare the effect of pharmacologic inhibition of 3 different catalytic domains of fatty acid synthase (FASN) on the cell cycle and apoptosis and associate with the morphologic alterations in squamous cell carcinoma 9 (SCC-9) cells. SCC-9 cells were treated with C75, triclosan (TCS), and orlistat (ORL) (inhibitors of KS, ER, and TE domains of FASN) for 24 to 48 hours and analyzed by flow cytometry and phase contrast microscopy. FASN inhibition with C75, ORL means Orlistat; TCS means Triclosan induced different effects on the morphology of SCC-9 cells. Cells treated with ORL showed a fusiform pattern. Instead, TCS induced the formation of cytoplasmic granules and C75 promoted a decrease of cell area. Also, the treatments reduced the number of cells in the S phase and increased the number of cells in the G0/G1 phase. Also, we observed an increase of apoptotic cells and a decrease of viable cells, which was observed in 3 different concentrations of all the drugs. However, TCS showed higher effectiveness in the apoptosis of SCC-9 cells. The morphologic changes of each inhibitor were linked not only to the specific inhibition of FASN activity but also could be due to adverse effects caused by the drugs. FAPESP.

Cellular fatty acid synthase is required for late stages of HIV-1 replication

BackgroundLike all viruses, HIV-1 relies on host systems to replicate. The human purinome consists of approximately two thousand proteins that bind and use purines such as ATP, NADH, and NADPH. By virtue of their purine binding pockets, purinome proteins are highly druggable, and many existing drugs target purine-using enzymes. Leveraging a protein affinity media that uses the purine-binding pocket to capture the entire purinome, we sought to define purine-binding proteins regulated by HIV-1 infection.ResultsUsing purinome capture media, we observed that HIV-1 infection increases intracellular levels of fatty acid synthase (FASN), a NADPH-using enzyme critical to the synthesis of de novo fatty acids. siRNA mediated knockdown of FASN reduced HIV-1 particle production by 80%, and treatment of tissue culture cells or primary PBMCs with Fasnall, a newly described selective FASN inhibitor, reduced HIV-1 virion production by 90% (EC50 = 213 nM). Despite the requirement of FASN for nascent virion production, FASN activity was not required for intracellular Gag protein production, indicating that FASN dependent de novo fatty acid biosynthesis contributes to a late step of HIV-1 replication.ConclusionsHere we show that HIV-1 replication both increases FASN levels and requires host FASN activity. We also report that Fasnall, a novel FASN inhibitor that demonstrates anti-tumor activity in vivo, is a potent and efficacious antiviral, blocking HIV-1 replication in both tissue culture and primary cell models of HIV-1 replication. In adults, most fatty acids are obtained exogenously from the diet, thus making FASN a plausible candidate for pharmacological intervention. In conclusion, we hypothesize that FASN is a novel host dependency factor and that inhibition of FASN activity has the potential to be exploited as an antiretroviral strategy.

Inhibition of the thioesterase activity of human fatty acid synthase by 1,4- and 9,10-diones.

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10-anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the thioesterase (TE) domain of FASN. Inhibition of recombinant TE activity, inhibition of cellular FASN, and cytotoxicity in human prostate cancer cell lines and normal fibroblasts, is shown for the most potent inhibitors. Collectively, the data illustrate the novel inhibitory capacity of the 1,4-quinone and 9,10-anthraquinone pharmacophores against FASN.

Inhibition of FASN reduces the synthesis of medium-chain fatty acids in goat mammary gland

Fatty acid synthase (FASN) is known as a crucial enzyme of cellular de novo fatty acid synthesis in mammary gland which has been proved as the main source of short and medium-chain fatty acids of milk. However, the regulatory role of FASN in goat-specific milk fatty acids composition remains unclear. We cloned and analyzed the full-length of FASN gene from the mammary gland of Capra hircus (Xinong Saanen dairy goat) (DQ 915966). Comparative gene expression analysis suggested that FASN is predominantly expressed in fat, small intestine and mammary gland tissues, and expresses higher level at lactation period. Inhibition of FASN activity by different concentrations (0, 5, 15, 25 and 35 μM) of orlistat, a natural inhibitor of FASN, resulted in decreased expression of acetyl-CoA carboxylase α (ACCα), lipoprotein lipase and heart-type fatty acid binding protein (H-FABP) in a concentration-dependent manner in goat mammary gland epithelial cells (GMEC). Similar results were also obtained by silencing of FASN. Additionally, reduction of FASN expression also led to apparent decline of the relative content of decanoic acid (C10:0) and lauric acid (C12:0) in GMEC. Our study provides a direct evidence for inhibition of FASN reduces cellular medium-chain fatty acids synthesis in GMEC.

Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or dimethyl sulfoxide (DMSO) (vehicle) was administered intraperitoneally from d 2 to 6. Clinical parameters were monitored daily. Mice were euthanized on d 8 for histological evaluation and measurements of colon length, chemokine, cytokine and inflammatory mediator expression. C75 significantly reduced body weight loss from 23% to 15% on d 8, compared with the vehicle group. The fecal bleeding, diarrhea and colon histological damage scores in the C75-treated group were significantly lower than scores in the vehicle animals. Colon shortening was significantly improved after C75 treatment. C75 protected colon tissues from DSS-induced apoptosis by inhibiting caspase-3 activity. Macrophage inflammatory protein 2, keratinocyte-derived chemokine, myeloperoxidase activity and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β and IL-6) in the colon were significantly downregulated in the C75-treated group, compared with the vehicle group. Treatment with C75 in colitis mice inhibited the elevation of FASN, cyclooxygenase-2 and inducible nitric oxide synthase expression as well as IκB degradation in colon tissues. C75 administration alleviates the severity of colon damage and inhibits the activation of inflammatory pathways in DSS-induced colitis. Thus, inhibition of FASN may represent an attractive therapeutic potential for treating IBD.

Tumor growth retardation and chemosensitizing action of fatty acid synthase inhibitor orlistat on T cell lymphoma: Implication of reconstituted tumor microenvironment and multidrug resistance phenotype

BackgroundOrlistat, a fatty acid synthase (FASN) inhibitor, has been demonstrated to inhibit tumor cell survival. However, the mechanism(s) of its tumor growth retarding action against malignancies of hematological origin remains unclear. It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs. Therefore, the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma. MethodsTumor-bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin. Tumor progression and survival of tumor-bearing host were monitored along with analysis of tumor cell survival and apoptosis. Tumor ascitic fluid was examined for pH, NO and cytokines. Expression of genes and proteins was investigated by RT-PCR and western blot respectively. ROS was analyzed by DCFDA staining and FASN activity by spectrophotometry. ResultsOrlistat administration to tumor-bearing mice resulted in tumor growth retardation, prolonged life span, declined tumor cell survival and chemosensitization to cisplatin. It was accompanied by increased osmotic fragility, modulated acidosis, expression of ROS, NO, cytokines, MCT-1 and VH+ ATPase, Bcl2, Caspase-3, P53, inhibited FASN activity and declined expression of MDR and MRP-1 proteins. ConclusionOrlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype. General significanceThese observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin.

Evaluation of Antihypertensive and Antihyperlipidemic Effects of Bamboo Shoot Angiotensin Converting Enzyme Inhibitory Peptide in Vivo

Cardiovascular protective functions of bamboo shoot angiotensin converting enzyme (ACE) inhibitory peptide (BSP) from bamboo shoot were evaluated, including antihypertensive effect on spontaneously hypertensive rats (SHRs) and antihyperlipidemic effect on high-fat-diet-induced rats. Thirty-day antihypertensive effects of BSP on SHRs were assayed. Asp-Tyr [10 mg/day kg body weight (BW)] and BSP (50 mg/day kg BW) significantly reduced ACE activity in lung at the same level (p < 0.05), while BSP (50 mg/day kg BW) reduced systolic blood pressure (SBP) more effectively for its phenolic compounds, such as ferulic acid and p-coumaric acid, which when combined with ACE inhibitor exert a synergistic effect. BSP could significantly reduce SBP, improve oxidant stress status (GSH-Px, SOD, TAC and MDA), and increase NO level in serum and NOS activity in kidney. BSP decreased total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c) content and MDA level of hyperlipidemic rats, which might contribute to the ACE inhibitory capacity of Asp-Tyr and the fatty acid synthase inhibitory activity of phenolic compounds.

A new furostanol glycoside with fatty acid synthase inhibitory activity from Ophiopogon japonicusa

A new furostanol glycoside, named ophiopogonin J (1), was isolated from the fibrous root of Ophiopogon japonicas. The structure of the compound was established as (25R)-26-[(O-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranosyl)]-20α -hydroxyfurost-5, 22-diene-3-O-α-L-rhamnopyranosyl-(1 → 2)-[β-D-xylopyranosyl(1 → 4)]-β-D-glucopyranoside on the basis of spectroscopic methods, including HR-ESI-MS and 1D and 2D NMR experiments.

New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity

Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5-30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC(50) < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.

Fatty acid synthase inhibitors isolated from Punica granatum L.

The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC50 value of 10.3 µmol L-1.

Bioassay-guided isolation of fatty acid synthase inhibitory diterpenoids from the roots of Salvia miltiorrhiza Bunge

Fatty acid synthase (FAS) is considered as a novel drug target for the development of anticancer and anti-obesity agents. Bioassay-guided fractionation of a n-hexane-soluble extract prepared from the roots of Salvia miltiorrhiza Bunge (Labiatae), using an in vitro enzyme assay, led to the isolation of five abietane diterpenoids: 15,16-dihydrotanshinone I (1), cryptotanshinone (2), tanshinone I (3), tanshinone IIA (4), and dansenspiroketallactone (5). Compounds 1-5 were tested for their in vitro FAS inhibitory activity and, except for compound 5 (IC(50) > 100 μM), compounds 1-4 inhibited the enzyme activity with IC(50) values ranging from 12.0 to 30.3 μM. Our findings may be partially related to the anticancer activity of abietane diterpenoids from the plant, suggesting a further study on the anticancer potential of tanshinone derivatives.

Inhibition of fatty acid synthase by ginkgolic acids from the leaves of Ginkgo biloba and their cytotoxic activity

Fatty acid synthase (FAS) has been proposed to be a new drug target for the development of anticancer agents because of the significant difference in expression of FAS between normal and tumour cells. Since a n-hexane-soluble extract from Ginkgo biloba was demonstrated to inhibit FAS activity in our preliminary test, we isolated active compounds from the n-hexane-soluble extract and evaluated their cytotoxic activity in human cancer cells. Three ginkgolic acids 1–3 isolated from the n-hexane-soluble extract inhibited the enzyme with IC50 values 17.1, 9.2 and 10.5 µM, respectively, and they showed cytotoxic activity against MCF-7 (human breast adenocarcinoma), A549 (human lung adenocarcinoma) and HL-60 (human leukaemia) cells. Our findings suggest that alkylphenol derivatives might be a new type of FAS inhibitor with cytotoxic activity.