Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

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)
  • Published : 2015.10.06
Download PDF
⟨ Previous Next ⟩

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

References

  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. https://doi.org/10.1016/j.fct.2007.09.085
  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. https://doi.org/10.1016/j.nutres.2011.01.006
  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. https://doi.org/10.1016/j.bcp.2012.08.011
  6. Elmore S (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol, 35, 495-516. https://doi.org/10.1080/01926230701320337
  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. https://doi.org/10.1016/j.fct.2010.12.010
  8. Guertin DA, Sabatini DM (2007). Defining the role of mTOR in cancer. Cancer Cell, 12, 9-22. https://doi.org/10.1016/j.ccr.2007.05.008
  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. https://doi.org/10.1158/1078-0432.CCR-09-1249
  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. https://doi.org/10.7314/APJCP.2014.15.11.4651
  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. https://doi.org/10.1186/1471-2164-15-74
  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. 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. https://doi.org/10.1371/journal.pone.0072365
  14. Jemal A, Bray F, Center M, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  15. 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. https://doi.org/10.1016/j.fitote.2010.07.024
  16. 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. https://doi.org/10.1093/carcin/19.3.419
  17. Khan KH, Yap TA, Cunningham D (2013). Targeting the PI3KAKT-mTOR signaling network in cancer. Chin J Cancer, 32, 253-65. https://doi.org/10.5732/cjc.013.10057
  18. Klein EA, Assoian RK (2008). Transcriptional regulation of the cyclin D1 gene at a glance. J Cell Sci, 121, 3853-7. https://doi.org/10.1242/jcs.039131
  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. https://doi.org/10.3390/ijms15022722
  21. Majumdar APN, Nautiyal J, Banerjee S, et al (2009). Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr Cancer, 61, 544-53. https://doi.org/10.1080/01635580902752262
  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. Mologni L, Brussolo S, Ceccon M, et al (2012). Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells. PLoS ONE, 7, 51449. https://doi.org/10.1371/journal.pone.0051449
  24. Moran A, Ortega P, Juan C, et al (2010). Differential colorectal carcinogenesis: Molecular Basis and clinical relevance. World J Gastrointest Oncol, 2, 151-8. https://doi.org/10.4251/wjgo.v2.i3.151
  25. 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. https://doi.org/10.1002/ijc.10202
  26. 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. https://doi.org/10.1186/1476-4598-8-100
  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. https://doi.org/10.1016/j.bbrc.2004.12.151
  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. https://doi.org/10.1186/1471-2407-11-154
  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. https://doi.org/10.1158/1078-0432.CCR-04-2014
  31. 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. https://doi.org/10.1158/1078-0432.CCR-04-2014
  32. Shukla Y, Singh M (2007). Cancer preventive properties of ginger: A brief review. Food Chem Toxicol, 45, 683-90. https://doi.org/10.1016/j.fct.2006.11.002
  33. 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. https://doi.org/10.1016/j.ejca.2010.07.026
  34. 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. https://doi.org/10.1016/S0278-6915(02)00037-6
  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. https://doi.org/10.1186/s12937-015-0015-2
  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. https://doi.org/10.7314/APJCP.2012.13.4.1605
  37. The Cancer Genome Atlas Network (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487, 330-7. https://doi.org/10.1038/nature11252
  38. Vara JAF, Casado E, Castro J, et al (2004). PI3K/Akt signalling pathway and cancer. Cancer Treatment Rev, 30, 193-204. https://doi.org/10.1016/j.ctrv.2003.07.007
  39. Wong SY (2011). Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res, 30, 87. https://doi.org/10.1186/1756-9966-30-87
  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. https://doi.org/10.1016/j.critrevonc.2012.11.009
  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. https://doi.org/10.1371/journal.pone.0091231
  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.

Cited by

  1. Insights into Putative Health Implications of Gelam (Melaleuca cajuputi) Honey: Evidence from In-Vivo and In-Vitro Studies vol.4, pp.1, 2016, https://doi.org/10.3390/medsci4010003
  2. Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms pp.1436-6215, 2017, https://doi.org/10.1007/s00394-017-1382-6
  3. Strawberry-Tree Honey Induces Growth Inhibition of Human Colon Cancer Cells and Increases ROS Generation: A Comparison with Manuka Honey vol.18, pp.3, 2017, https://doi.org/10.3390/ijms18030613
  4. Inhibition of mTOR/S6K1/4E-BP1 Signaling by Nutraceutical SIRT1 Modulators vol.70, pp.3, 2018, https://doi.org/10.1080/01635581.2018.1446093
  5. Enhancing the Anticancer Activity of Antrodia cinnamomea in Hepatocellular Carcinoma Cells via Cocultivation With Ginger: The Impact on Cancer Cell Survival Pathways vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.00780
  6. Combinatorial Cytotoxic Effects of Gelam Honey and 5-Fluorouracil against Human Adenocarcinoma Colon Cancer HT-29 Cells In Vitro vol.2019, pp.1687-8884, 2019, https://doi.org/10.1155/2019/3059687
  7. Immunomodulatory Effects of Flavonoids: Possible Induction of T CD4+ Regulatory Cells Through Suppression of mTOR Pathway Signaling Activity vol.10, pp.1664-3224, 2019, https://doi.org/10.3389/fimmu.2019.00051