Abstract A24: Mechanistic investigation of the anti-cancer and anti-hyperlipidemia effects of Gynostemma triterpenoids using systems biology approach

Abstract

Abstract Triterpenoids, produced in many plants, are widely used in Asian medicine. Gynostemma pentaphyllum (Gp), also called jiaogulan, is a rich source of dammarane-type triterpenoids (GpS) and is used as a traditional Chinese herbal medicine for the treatment of various diseases including cancer and hyperlipidemia. However, the proven efficacy and the underlying mechanism have not been investigated systematically. We have been investigating the anticancer activities of GpS using in vitro and in vivo models. We found that GpS effectively inhibits the growth of tumor cells. Intriguingly, inhibitory effects of GpS require the presence of co-cultivated normal cells. In animal study, GpS treatment markedly reduced the numbers and sizes of polyps in Apcmin/+ mice, a commonly used mouse model for colorectal cancer, manifest both high number of intestinal polyps and hyperlipidemia. We also found that GpS can effectively suppress plasma triglycerides and cholesterol levels in Apcmin/+ mice. To delineate the precise mechanisms of the anticancer and antihyperlipidemia effects of GpS, we performed molecular and proteomic analysis of mouse plasma and liver tissue treated with or without GpS and cDNA microarray analysis for cell line. Proteomic and cDNA microarray analyses revealed that a wide spectrum of glycolytic and energy metabolic gene products were downregulated in cells and liver tissue treated with GpS. Molecular study results showed that lipoprotein lipase, PPARα, PPARγ and adiponectin were upregulated and HMG-CoA reductase was downregulated upon GpS treatment. Plasma protein profiling revealed that several downregulated proteins were directly related to cancer, inflammatory, cell proliferation and four lipogenesis were downregulated. Moreover, we also investigated the combinatorial effect of GpS with 5-FU. We found that combined treatment further reduced the intestinal polyps in all regions of intestine. Strikingly, the combined treatment almost completely suppressed small intestinal polyps. Such efficacy cannot be achieved with 5-FU alone. We further used cDNA microarray experiments to further investigate the gene expressions profiles of liver tissue between GpS, 5-FU and combined treatments in Apcmin/+ mice. In the case of GpS, 125 differentially expressed genes were identified (>2-fold; p<0.05)) as compared with no treatment; 374 genes were found at 5-FU treatment; 431 genes were found at combined treatment. Based on the KEGG pathway and GO analysis, among the differentially genes expressed of GpS treatment, genes were involved in PPAR, Wnt, MAPK, p53 and Insulin signaling pathways, cell cycle, regulation of actin cytoskeleton, lipid metabolic process and humoral immune response. For 5-FU treatment, genes were involved in PPAR, p53, ATM, insulin, MAPK, IL-6 signaling pathways, cell cycle and glutathione metabolism. For the combined treatment, genes were involved in PPAR, p53, TGF-β, FAS, p38MAPK signaling pathways, cell cycle, glutathione metabolism, and chemokine activity. Surprisingly, only 17 of these differentially expressed genes were common in GpS, 5-FU and combined treatments. Further analysis will be presented in the meeting. In conclusion, the data shown above (1) provide solid evidence of the anticancer and antihyperlipidemia effects of GpS; (2) provide a conceptually novel approach by which the growth of cancer cells can be suppressed through the reduction of cellular glycolytic activities; (3) botanical tripterpenoids can be potentially used as adjuvant chemotherapy in combination of 5-FU for the treatment of colorectal cancer. [This study was partially supported by Research Grants Council of Hong Kong under HKBU2/07C and HKBU 260307 Grants to WLWH.] Citation Format: William Chi Shing Tai, Wing Yan Wong, Jen Fu Chiu, Wen Luan Wendy Hsiao. Mechanistic investigation of the anti-cancer and anti-hyperlipidemia effects of Gynostemma triterpenoids using systems biology approach [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A24.