6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ)

Tan, Boon Shing; Kang, Owen; Wu, Chun; Tiong, Kai Hung; Khoo, Alan Soo‐Beng; Pichika, Mallikarjuna Rao; Bradshaw, Tracey D.; Leong, Chee‐Onn

doi:10.1016/j.canlet.2013.04.014

Cited by 83 publications

(68 citation statements)

References 65 publications

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“…Genes which were up- or down-regulated ≥2-fold in treated cells compared to control cells were identified. The data were further analyzed by Connectivity Map analyses (CMap) [20, 26–28]. The results obtained from the CMap were further corroborated with target prediction results by SwissTargetPrediction (http://www.swisstargetprediction.ch/) [29, 30].…”

Section: Methodsmentioning

confidence: 87%

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Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway

et al. 2017

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Cudraflavone C (Cud C) is a naturally-occurring flavonol with reported anti-proliferative activities. However, the mechanisms by which Cud C induced cytotoxicity have yet to be fully elucidated. Here, we investigated the effects of Cud C on cell proliferation, caspase activation andapoptosis induction in colorectal cancer cells (CRC). We show that Cud C inhibits cell proliferation in KM12, Caco-2, HT29, HCC2998, HCT116 and SW48 CRC but not in the non-transformed colorectal epithelial cells, CCD CoN 841. Cud C induces tumor-selective apoptosis via mitochondrial depolarization and activation of the intrinsic caspase pathway. Gene expression profiling by microarray analyses revealed that tumor suppressor genes EGR1, HUWE1 and SMG1 were significantly up-regulated while oncogenes such as MYB1, CCNB1 and GPX2 were down-regulated following treatment with Cud C. Further analyses using Connectivity Map revealed that Cud C induced a gene signature highly similar to that of protein synthesis inhibitors and phosphoinositide 3-kinase (PI3K)-AKT inhibitors, suggesting that Cud C might inhibit PI3K-AKT signaling. A luminescent cell free PI3K lipid kinase assay revealed that Cud C significantly inhibited p110β/p85α PI3K activity, followed by p120γ, p110δ/p85α, and p110α/p85α PI3K activities. The inhibition by Cud C on p110β/p85α PI3K activity was comparable to LY-294002, a known PI3K inhibitor. Cud C also inhibited phosphorylation of AKT independent of NFκB activity in CRC cells, while ectopic expression of myristoylated AKT completely abrogated the anti-proliferative effects, and apoptosis induced by Cud C in CRC. These findings demonstrate that Cud C induces tumor-selective cytotoxicity by targeting the PI3K-AKT pathway. These findings provide novel insights into the mechanism of action of Cud C, and indicate that Cud C further development of Cud C derivatives as potential therapeutic agents is warranted.

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Section: Methodsmentioning

confidence: 87%

“…All media contained 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (Sigma-Aldrich, USA). Cells were cultured in a dedicated cell culture incubator at 37°C, 5% CO 2 using standard cell culture methods optimized in previous studies [20, 21]. …”

Section: Methodsmentioning

confidence: 99%

Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway

et al. 2017

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“…39−42 Our group and others have identified active constituents of ginger, with our most recent focus on shogaols, especially 6S. 12,13,19,20,23,39,43,44 The metabolism and biotransformation of 6S was investigated thoroughly, providing further insight into its means of exerting bioactivity. 19 Upon testing the efficacy of the major metabolites of 6S, we found that 5-cysteinyl-conjugated 6S (M2) exerted strong antiproliferative activity against human colon cancer cells, while having significantly lessened toxicity in normal human colon cells.…”

Section: Discussionmentioning

confidence: 99%

Cysteine-Conjugated Metabolites of Ginger Components, Shogaols, Induce Apoptosis through Oxidative Stress-Mediated p53 Pathway in Human Colon Cancer Cells

Chen

Soroka

et al. 2014

J. Agric. Food Chem.

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Shogaols, the major constituents of thermally processed ginger, have been proven to be highly effective anticancer agents. Our group has identified cysteine-conjugated shogaols (M2, M2′, and M2″) as the major metabolites of [6]-, [8]-, and [10]-shogaol in human and found that M2 is a carrier of its parent molecule [6]-shogaol in cancer cells and in mice, while being less toxic to normal colon fibroblast cells. The objectives of this study are to determine whether M2′ and M2″ behave in a similar manner to M2, in both metabolism and efficacy as anticancer agents, and to further explore the biological pro-apoptotic mechanisms of the cysteine-conjugated shogaols against human colon cancer cells HCT-116 and HT-29. Our results show that [8]- and [10]-shogaol have similar metabolic profiles to [6]-shogaol and exhibit similar toxicity toward human colon cancer cells. M2′ and M2″ both show low toxicity against normal colon cells but retain potency against colon cancer cells, suggesting that they have similar activity to M2. We further demonstrate that the cysteine-conjugated shogaols can cause cancer cell death through the activation of the mitochondrial apoptotic pathway. Our results show that oxidative stress activates a p53 pathway that ultimately leads to p53 up-regulated modulator of apoptosis (PUMA) induction and down-regulation of B-cell lymphoma 2 (Bcl-2), followed by cytochrome c release, perturbation of inhibitory interactions of X-linked inhibitor of apoptosis protein (XIAP) with caspases, and finally caspase 9 and 3 activation and cleavage. A brief screen of the markers attenuated by the proapoptotic activity of M2 revealed similar results for [8]- and [10]-shogaol and their respective cysteine-conjugated metabolites M2′ and M2″. This study highlights the cysteine-conjugated metabolites of shogaols as novel dietary colon cancer preventive agents.

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“…Inhibition of cell proliferation by the isolated compounds was determined by using the methyl thiazolyl tetrazolium (MTT) cell viability assay, as described previously with slight modification (Tan et al, 2013;Low et al, 2012). 5-Fluorouracil was used as a positive control in the assay.…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

In vitro cytotoxic activity of isolated compounds from Malaysian Calophyllum species

et al. 2016

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Cancer is a leading cause of death worldwide. In our continuing search for new anticancer agents, four Malaysian Calophyllum species, namely C. castaneum, C. teysmannii, C. canum, and C. sclerophyllum, had been phytochemically studied to give compounds 1-12. All the isolated compounds were evaluated for their antiproliferative activity against nasopharyngeal (SUNE1, TW01, CNE1, HK1) and breast (HCC38, MDA-MB-231, MDA-MB-468, SKBR3) cancer cell lines via methyl thiazolyl tetrazolium cell viability assay. Among the tested compounds, isodispar B (1) showed a promising dosedependent and a broad spectrum of cytotoxic effects on all the tested cancer cell lines; in particular, potent inhibitory activities were observed on nasopharyngeal cancer cell lines (SUNE1, TW01, CNE1, HK1), with IC 50 values ranging from 3.8 to 11.5 µM. In comparison with 5-fluorouracil as positive control, compound 1 was found to exhibit at least sixfold much higher activity than the standard drug used against the nasopharyngeal cell lines. Compound 1 was later found to induce apoptotic cell death in nasopharyngeal cancer cells, as evidenced by 'Cell Death Detection' ELI-SA PLUS kit, and exhibited good cancer-specific cytotoxicity when tested with noncancerous NP460 cells. Meanwhile, compounds 2-12 displayed moderate to weak activities against the tested cancer cell lines. The findings have highlighted the therapeutic potential of compound 1 against nasopharyngeal cancer.

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6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ)

Cited by 83 publications

References 65 publications

Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway

Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway

Cysteine-Conjugated Metabolites of Ginger Components, Shogaols, Induce Apoptosis through Oxidative Stress-Mediated p53 Pathway in Human Colon Cancer Cells

In vitro cytotoxic activity of isolated compounds from Malaysian Calophyllum species

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