Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells

Abstract

BackgroundFatty acid synthase (FAS) has been proven over-expressed in human breast cancer cells and consequently, has been recognized as a target for breast cancer treatment. Alpha-mangostin, a natural xanthone found in mangosteen pericarp, has a variety of biological activities, including anti-cancer effect. In our previous study, alpha-mangostin had been found both fast-binding and slow-binding inhibitions to FAS in vitro. This study was designed to investigate the activity of alpha-mangostin on intracellular FAS activity in FAS over-expressed human breast cancer cells, and to testify whether the anti-cancer activity of alpha-mangostin may be related to its inhibitory effect on FAS.MethodsWe evaluated the cytotoxicity of alpha-mangostin in human breast cancer MCF-7 and MDA-MB-231 cells. Intracellular FAS activity was measured by a spectrophotometer at 340 nm of NADPH absorption. Cell Counting Kit assay was used to test the cell viability. Immunoblot analysis was performed to detect FAS expression level, intracellular fatty acid accumulation and cell signaling (FAK, ERK1/2 and AKT). Apoptotic effects were detected by flow cytometry and immunoblot analysis of PARP, Bax and Bcl-2. Small interfering RNA was used to down-regulate FAS expression and/or activity.ResultsAlpha-mangostin could effectively suppress FAS expression and inhibit intracellular FAS activity, and result in decrease of intracellular fatty acid accumulation. It could also reduce cell viability, induce apoptosis in human breast cancer cells, increase in the levels of the PARP cleavage product, and attenuate the balance between anti-apoptotic and pro-apoptotic proteins of the Bcl-2 family. Moreover, alpha-mangostin inhibited the phosphorylation of FAK. However, the active forms of AKT, and ERK1/2 proteins were not involved in the changes of FAS expression induced by alpha-mangostin.ConclusionsAlpha-mangostin induced breast cancer cell apoptosis by inhibiting FAS, which provide a basis for the development of xanthone as an agent for breast cancer therapy.

In vitro and in vivo characterization of the anticancer activity of Thai stingless bee (Tetragonula laeviceps) cerumen

“…29 It has previously been shown that -mangostin suppresses the expression and intracellular activity of fatty acid synthase, a metabolic enzyme commonly over-expressed in various cancer cell lines and crucial for their survival. 30 Additionally, -mangostin can inhibit mammalian DNA polymerase and topoisomerases, which may also contribute to its stronger toxicity towards rapidly dividing cancer cells. 31 Our data support a potential chemopreventive and chemotherapeutic potential of -mangostin for cancer treatment, but this requires further tissue specific and in vivo confirmation.…”

Patuletin induces apoptosis of human breast cancer SK‑BR‑3 cell line via inhibiting fatty acid synthase gene expression and activity

“…According to the close association between FASN, obesity and breast cancer, the studies of FASN inhibitors have indicated their role as targets for chemotherapy in breast cancer and a novel strategy for antineoplastic intervention (18). In fact, previous studies demonstrated that certain synthetic and natural FASN inhibitors, including C75, desoxyrhaponticin, rhaponticin and α-mangostin may lead to selective cytotoxicity in FASN over-expressing cancer cell lines (18)(19)(20). This result suggested again that the pharmacological inhibition of FASN may represent a potential target for drug development.…”

“…SK-BR-3 cells were seeded in 96-well plate firstly, at a density about 5x10 3 cells/well and then treated with purified patuletin in different concentrations (5,10,20,40, 80 or 160 µM) for 24 h. Thereafter, 5 mg/ml MTT solution was added into each well and incubated for 4 h at 37˚C. Then, the medium with MTT was aspirated, 200 µl DMSO/well was added to the wells and the cells were incubated for 15 min.…”

Effect of Curcumin on Fatty Acid Synthase Expression and Enzyme Activity in Breast Cancer Cell Line SKBR3

“…Several studies have shown that inhibition of FAS may induce cell apoptosis via reducing fatty acids (12,14,32) These results support the significant role of FAS in SK-BR-3 cells and propose that FAS is the aim that curcumin act on.…”

“…50 µL Particlefree supernatant, 25 mM potassium Phosphate buffer, 0.25 mM EDTA, 0.25 mM dithiothreitol (DTT), 30 µM acetyl-CoA, and 350 µM NADPH (pH 7.0) in a total volume of 500 µL were Observed at 340 nm for 100 s to measure NADPH oxidation. After the addition of 100 µM of malonyl-CoA, the reaction was tested for an additional 1 minutes to designate FAS-dependent oxidation of NADPH (14). The change in concentration of NADPH during oxidation was measured using the following formula: ∆C = ∆A/E…”