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http://dx.doi.org/10.7314/APJCP.2015.16.15.6549

Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/β-catenin Pathways  

Wee, Lee Heng (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
Morad, Noor Azian (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
Aan, Goon Jo (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
Makpol, Suzana (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
Ngah, Wan Zurinah Wan (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
Yusof, Yasmin Anum Mohd (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.16, no.15, 2015 , pp. 6549-6556 More about this Journal
Abstract
The PI3K-Akt-mTOR, $Wnt/{\beta}$-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, $Wnt/{\beta}$-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with $IC_{50}$ values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, ${\beta}$-catenin, $Gsk3{\beta}$, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, $Wnt/{\beta}$ catenin signaling pathways and induction of apoptosis pathway.
Keywords
mTOR; $Wnt/{\beta}$ catenin; apoptosis; combination; HT29 colon cancer cells;
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1 Abdullah S, Abidin SAZ, Murad NA, et al (2010). Ginger extract (Zingiber officinale) triggers apoptosis and G0/G1 cells arrest in HCT 116 and HT 29 colon cancer cell lines. Afric J Biochem Res, 4, 134-42.
2 Ali BH, Blunden G, Tanira MO, et al (2008). Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): A review of recent research. Food Chem Toxicol, 46, 409-20.   DOI
3 Amundson SA, Myers TG, Scudiero D, et al (2000). An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res, 60, 6101-10.
4 Araujo JR, Goncalves P, Martel F (2011). Chemopreventive effect of dietary polyphenols in colorectal cell lines. Nutr Res, 31, 77-87.   DOI   ScienceOn
5 Chen HJ, Hsu LS, Shia YT, et al (2012). The $\beta$-catenin/Tcf complex as a novel target of resveratrol in the Wnt/$\beta$-catenin signaling pathway. Biochemical Pharmacol, 84, 1143-53.   DOI
6 Elmore S (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol, 35, 495-516.   DOI
7 Fauzi AN, Norazmi MN, Taacob NS (2011). Tualang honey induces apoptosis and disrupts the mitochondrial membrane potential of human breast and cervical cancer cell lines. Food Chem Toxicol, 49, 871-8.   DOI
8 Guertin DA, Sabatini DM (2007). Defining the role of mTOR in cancer. Cancer Cell, 12, 9-22.   DOI
9 Gulhati P, Cai QS, Li J, et al (2009). Targeted inhibition of mTOR signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res, 15, 7207-16.   DOI
10 Hakim L, Alias E, Makpol S, et al (2014). Gelam honey and ginger potentiate the anti cancer effect of 5-FU against HCT116 colorectal cancer cells. Asia Pac J Cancer Prev, 15, 4651-7.   DOI
11 Herbst A, Jurinovic V, Krebs S, et al (2014). Comprehensive analysis of $\beta$-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/$\beta$-catenin signaling. BMC Genomics, 15, 74.   DOI
12 Hussein SZ, Yusoff KM, Makpol S, et al (2012). Gelam honey inhibits the production of proinflammatory, mediators NO, PGE2, TNF-$\alpha$, and IL-6 in carrageenan-induced acute paw edema in rats. Evid Based Compl Alt Med, 2012, 109636.
13 Khafif A, Schantz SP, Chou TC, et al (1998). Quantitation of chemopreventive synergism between (-)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant human oral epithelial cells. Carcinogenesis, 19, 419-24.   DOI
14 Hussein SZ, Yusoff KM, Makpol S, et al (2013). Gelam honey attenuates carrageenan-induced rat paw inflammation via NF-${\kappa}B$ pathway. PLoS ONE, 8, 72365.   DOI
15 Jemal A, Bray F, Center M, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.   DOI
16 Kassim M, Achoui M, Mansor M, et al (2010). The inhibitory effects of Gelam honey and its extracts on nitric oxide and prostaglandin E2 in inflammatory tissues. Fitoterapia, 81, 1196-201.   DOI   ScienceOn
17 Khan KH, Yap TA, Cunningham D (2013). Targeting the PI3KAKT-mTOR signaling network in cancer. Chin J Cancer, 32, 253-65.   DOI
18 Klein EA, Assoian RK (2008). Transcriptional regulation of the cyclin D1 gene at a glance. J Cell Sci, 121, 3853-7.   DOI
19 Kumar A, Pandurangan AK, Lu F, et al (2012). Chemopreventive sphingadienes downregulate Wnt signaling via PP2A/Akt/ GSK3$\beta$ pathway in colon cancer. Carcinogenesis, 1-38.
20 Lee HS, Cho HJ, Yu R, et al (2014). Mechanisms underlying apoptosis-inducing effects of kaempferol in HT-29 human colon cancer cells. Int J Mol Sci, 15, 2722-37.   DOI
21 Majumdar APN, Nautiyal J, Banerjee S, et al (2009). Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr Cancer, 61, 544-53.   DOI
22 Mandal P, Misra TK, Ghosal M (2009). Free-readical scavenging activity and phytochemical analysis in the leaf and stem of Drymaria diandra Blume. Int J Integ Biol, 7, 80-4.
23 Nakamura Y, Yogosawa S, Izutani Y, et al (2009). A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Molec Cancer, 8, 100.   DOI
24 Mologni L, Brussolo S, Ceccon M, et al (2012). Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells. PLoS ONE, 7, 51449.   DOI
25 Moran A, Ortega P, Juan C, et al (2010). Differential colorectal carcinogenesis: Molecular Basis and clinical relevance. World J Gastrointest Oncol, 2, 151-8.   DOI
26 Mouria M, Gukovskaya AS, Jung Y, et al (2002). Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome c release and apoptosis. Int J Cancer, 98, 761-9.   DOI
27 Palmer HJ, Paulson KE (1997). Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr Rev, 55, 353-61.
28 Park CH, Chang JY, Hahm ER, et al (2005). Quercetin, a potent inhibitor against $\beta$-catenin/Tcf signaling in SW480 colon cancer cells. Biocheml Biophys Res Comm, 328, 227-34.   DOI
29 Reyes-Zurita FJ, Pachon-Pena G, Lizarraga D, et al (2011). The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism. BMC Cancer, 11, 154.   DOI
30 Shimuzu M, Deguchi A, Lim TE (2005). (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res, 11, 2735-46.   DOI
31 Surh YJ (2002). Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review. Food Chem Toxicol, 40, 1091-7.   DOI
32 Shimuzu M, Deguchi A, Lim TE (2005). (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res, 11, 2735-46.   DOI
33 Shukla Y, Singh M (2007). Cancer preventive properties of ginger: A brief review. Food Chem Toxicol, 45, 683-90.   DOI
34 Soerjomataram I, Oomen D, Lemmens V, et al (2010). Increased consumption of fruit and vegetables and future cancer incidence in selected European countries. Eur J Cancer, 46, 2563-80.   DOI
35 Tahir AA, Abdul Sani NF, Morad NA, et al. (2015). Combined ginger extract & Gelam honey modulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells. Nutr J, 14, 31.   DOI
36 Teh PW, Hussein SZ, Abdullah S, et al (2012). Gelam and nenas honeys inhibit proliferation of HT29 colon cancer cells by inducing DNA damage and apoptosis while suppressing inflammation. Asia Pac J Cancer Prev, 13, 1605-10.   DOI   ScienceOn
37 The Cancer Genome Atlas Network (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487, 330-7.   DOI   ScienceOn
38 Vara JAF, Casado E, Castro J, et al (2004). PI3K/Akt signalling pathway and cancer. Cancer Treatment Rev, 30, 193-204.   DOI
39 Wong SY (2011). Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res, 30, 87.   DOI
40 Wu KK, Wang XJ, Cheng SL, et al (2013). Dysregulation and crosstalk of cellular signaling pathways in colon carcinogenesis. Crit Rev Oncol/Hematol, 86, 251-77.   DOI
41 Zainal AO, Nor Saleha IT (2011). National cancer registry report Malaysia Cancer statistics 2007. ministry of health Malaysia.
42 Zeng J, Liu D, Qiu Z, et al (2014). GSK3$\beta$ overexpression indicates poor prognosis and its inhibition reduces cell proliferation and survival of non-small cell lung cancer cells. PLoS ONE, 9, 91231.   DOI
43 Zhang J, Liu Z, Huang Y, et al (2013). GSK3$\beta$ overexpression indicated poor prognosis and its inhibition reduces cell proliferation and survival of non-small cell lung cancer cells. PLoS ONE, 9, 91231.