Article

Inhibition of fatty acid synthase by Orlistat accelerates gastric tumor cell apoptosis in culture and increases survival rates in gastric tumor bearing mice in vivo.

Biochemistry, A.T. Still University of the Health Sciences, Kirksville, USA.
Lipids (Impact Factor: 2.35). 05/2009; 44(6):489-98. DOI: 10.1007/s11745-009-3298-2
Source: PubMed

ABSTRACT Orlistat, an anti-obesity drug, is a potent inhibitor of fatty acid synthase (FAS) and tumor cell viability. It can also induce apoptotic cancer cell death. We examined the effects of Orlistat on cultured NUGC-3 gastric cancer cells. We identified that inhibition of FAS via Orlistat exposure results in rapid cellular damage preceded by a direct but short-lived autophagic response. The Orlistat induced damage can be reversed through the addition of lipid containing media in a process that normally leads to cell death. By limiting exogenous lipid availability and inhibiting FAS using Orlistat, we demonstrated both a greater sensitivity and amplified cancer cell death by activation of apoptosis. We have identified "windows of opportunity" at which time apoptosis can be aborted and cells can be reversed from the death pathway. However, when challenged beyond the window of recovery, cell death becomes all but certain as the ability to be rescued decreases considerably. In vivo examination of Orlistat's ability to inhibit gastrointestinal cancer was examined using heterozygous male C57BL/6J APC-Min mice, which spontaneously develop a fatal gastrointestinal cancer. Mice were fed either a high fat (11%) or low fat (1.2%) diet containing no Orlistat or 0.5 mg Orlistat/g of chow. Orlistat treated mice fed the high fat, but not low fat diet, survived 7-10% longer than the untreated controls.

0 Followers
 · 
193 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: A concise enantioselective synthesis of tetrahydrolipstatin (THL) and eight stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid]+[Co(CO)4]- catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.
    Journal of the American Chemical Society 07/2014; 46(10). DOI:10.1021/ja505639u · 11.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce apoptosis in non-tumorigenic cells via mitochondrial dysfunction, independent of FASN inhibition.
    PLoS ONE 06/2014; 9(6):e101060. DOI:10.1371/journal.pone.0101060 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cells metabolically adapt to undergo cellular proliferation. Lipids, besides their well-known role as energy storage, represent the major building blocks for the synthesis of neo-generated membranes. There is increasing evidence that cancer cells show specific alterations in different aspects of lipid metabolism. The changes of expression and activity of lipid metabolizing enzymes are directly regulated by the activity of oncogenic signals. The dependence of tumour cells on the deregulated lipid metabolism suggests that proteins involved in this process could be excellent chemotherapeutic targets for cancer treatment. Due to its rare side effects in non-cancerous cells, metformin has been recently revaluated as potential anti-tumorigenic drug, which negatively affects lipid biosynthetic pathways. In this review we summarised the emerging molecular events linking the anti-proliferative effect of metformin with lipid metabolism in cancer cells.
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 04/2014; DOI:10.1016/j.bbcan.2014.02.003 · 7.58 Impact Factor

Preview

Download
3 Downloads
Available from