DOI QR코드

DOI QR Code

Gelam Honey and Ginger Potentiate the Anti Cancer Effect of 5-FU against HCT 116 Colorectal Cancer Cells

  • Hakim, Luqman (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia) ;
  • Alias, Ekram (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) ;
  • Morad, Nor Azian (Centre of Lipids and Engineering and Applied Research, Universiti Teknologi) ;
  • Yusof, Yasmin Anum Mohd (Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia)
  • Published : 2014.06.15

Abstract

The development of chemopreventive approaches using a concoction of phytochemicals is potentially viable for combating many types of cancer including colon carcinogenesis. This study evaluated the anti-proliferative effects of ginger and Gelam honey and its efficacy in enhancing the anti-cancer effects of 5-FU (5-fluorouracil) against a colorectal cancer cell line, HCT 116. Cell viability was measured via MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium) assay showing ginger inhibiting the growth of HCT 116 cells more potently ($IC_{50}$ of 3mg/mL) in comparison to Gelam honey ($IC_{50}$ of 75mg/mL). Combined treatment of the two compounds (3mg/mL ginger+75mg/mL Gelam honey) synergistically lowered the $IC_{50}$ of Gelam honey to 22mg/mL. Combination with 35 mg/mL Gelam honey markedly enhanced 5-FU inhibiting effects on the growth of HCT 116 cells. Subsequent analysis on the induction of cellular apoptosis suggested that individual treatment of ginger and Gelam honey produced higher apoptosis than 5-FU alone. In addition, treatment with the combination of two natural compounds increased the apoptotic rate of HCT 116 cells dose-dependently while treatment of either ginger or Gelam honey combined with 5-FU only showed modest changes. Combination index analysis showed the combination effect of both natural compounds to be synergistic in their inhibitory action against HCT 116 colon cancer cells (CI 0.96 < 1). In conclusion, combined treatment of Gelam honey and ginger extract could potentially enhance the chemotherapeutic effect of 5-FU against colorectal cancer.

References

  1. Abdullah S, Morad NA, Makpol S, et al (2010). Ginger extract (Zingiber officinale) triggers apoptosis and G0/G1 cell arrest in HCT 116 and HT29 colon cancer cell lines. Afr J Biochem Res, 4, 134-42.
  2. Aggarwal BB, Takada Y, Oommen OV (2004). From chemoprevetion to chemotherapy: common targets and common goal. Expert Opin Investig Drugs, 13, 1327-38. https://doi.org/10.1517/13543784.13.10.1327
  3. Ahmed S, Othman NH (2013). Honey as a potential natural anticancer agent: a review of its mechanism. Evid Based Complement Altern Med, eCAM 2013: 829070.
  4. Al-Waili N, Salom K, Al-Ghamdi AA (2011). Honey for wound healing, ulcers and burns; data supporting its use in clinical practice. Sci World J, 11, 766-87. https://doi.org/10.1100/tsw.2011.78
  5. Ali BH, Blunden G, Tanira MO, Nemmar A (2008). Some phytochemicals, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Biol Res Assoc, 46, 409-20.
  6. Brahmbhatt M, Gundala SR, Asif G, et al (2013). Ginger phytochemicals exhibit synergy to inhibit porstate cancer cell proliferation. Nutr Cancer, 65, 263-72. https://doi.org/10.1080/01635581.2013.749925
  7. Braun MS, Seymour MT (2011). Balancing the efficacy and toxicity of chemotherapy in colorectal cancer. Ther Adv Med Oncol, 3, 43-52. https://doi.org/10.1177/1758834010388342
  8. Cherchi A, Spanedda L, Tuberoso C, Cabras P (1994). Solid-phase extraction and high performance liquid chromatography determination of organic acids in honey. J Chromatogr A, 669, 59-64. https://doi.org/10.1016/0021-9673(94)80336-6
  9. Chou TC (2006). Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev, 58, 621-81. https://doi.org/10.1124/pr.58.3.10
  10. Chua LS, Rahaman NL, Adnan NA, Eddie Tan TT (2013). Antioxidant activity of three honey samples in relation with their biochemical components. J Anal Methods Chem, 2013, 313798.
  11. Douillard JY, Cunningham D, Roth AD, et al (2000). Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet, 355, 1041-7. https://doi.org/10.1016/S0140-6736(00)02034-1
  12. Gheldof N, Wang XH, Engeseth NJ (2002). Identification and quantification of antioxidant components of honeys from various floral sources. J Agr Food Chem, 50, 5870-7. https://doi.org/10.1021/jf0256135
  13. Fauzi AN, Norazmi MN, Yaacob 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
  14. Ferlay J, Shin HR, Bray F, et al (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 127, 2893-917. https://doi.org/10.1002/ijc.25516
  15. Fukuda M, Kobayashi K, Hirono Y, et al (2011). Jungle honey enhances immune function and antitumour activity. Evid Based Complement Alternat Med, 2011, 908743.
  16. Giacchetti S, Perpoint B, Zidani R, et al (2000). Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Onc, 18, 136-47.
  17. Grzanna R, Lindmark L, Frondoza CG (2005). Ginger-an herbal medicinal product with broad anti-inflammatory actions. J Med Food, 8, 125-32. https://doi.org/10.1089/jmf.2005.8.125
  18. Habib SH, Makpol S, Hamid A, et al (2008). Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effect on ethionine-induced hepatoma rats. Clinics (Sao Paolo, Brazil), 63, 807-13.
  19. Havsteen BH (2002). The biochemistry and medical significance of the flavonoids. Pharmacol Ther, 96, 67-202. https://doi.org/10.1016/S0163-7258(02)00298-X
  20. Hussein SZ, Mohd Yusoff K, Makpol S, Mohd Yusof YA (2012). Gelam honey inhibits the production of pro-inflammatory mediators NO, PGE(2), TNF-alpha, and IL-6 in carrageenan-induced acute paw edema in rats. Evid Based Complement Alternat Med, 2012, 109636.
  21. Jaganathan SK, Mazumdar A, Mondhe D, Mandal M (2011). Apoptotic effect of eugenol in human colon cancer cell lines. Cell Biol Int, 25, 607-15.
  22. Hussein SZ, Mohd Yusoff K, Makpol S, Mohd Yusof YA (2011). Antioxidant capacities and total phenolic contents increase with gamma irradiation in two types of Malaysian honey. Molecules, 16, 6378-95. https://doi.org/10.3390/molecules16086378
  23. Jaganathan SK, Mandal M (2009). Honey constituents and their apoptotic effect in colon cancer cells. J Api Product Api Med Sci, 1, 29-36. https://doi.org/10.3896/IBRA.4.01.2.02
  24. Jaganathan SK, Mandal M (2010). Involvement of non-protein thiols, mitochondrial dysfunction, reactive oxygen species and p53 in honey-induced apoptosis. Inv New Drugs, 28, 624-33. https://doi.org/10.1007/s10637-009-9302-0
  25. Jaganathan SK, Mondhe D, Wani ZA, et al (2010). Effect of honey and eugenol on Ehrlich ascites and solid carcinoma. J Biomed Biotechnol, 2010, 989163.
  26. Jaganathan SK, Supriyanto E, Mandal M (2013). Events associated with apoptotic effect of p-coumaric acid in HCT-15 colon cancer cells. World J Gastroenterol, 19, 7726-34. https://doi.org/10.3748/wjg.v19.i43.7726
  27. Jeong CH, Bode AM, Pugliese A, et al (2009). [6]-gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Res, 69, 5584-91. https://doi.org/10.1158/0008-5472.CAN-09-0491
  28. Jolad SD, Lantz RC, Solyom AM, et al (2004). Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochemistry, 65, 1937-54. https://doi.org/10.1016/j.phytochem.2004.06.008
  29. Kassim M, Achoui M, Mustafa MR, et al (2010). Ellagic acid, phenolic acids, and flavonoids in Malaysian honey extracts demonstrate in vitro anti-inflammatory activity. Nutr Res, 30, 650-9. https://doi.org/10.1016/j.nutres.2010.08.008
  30. Khalil MI, Alam N, Moniruzzaman M, et al (2011). Phenolic acid composition and antioxidant properties of Malaysian honeys. J Food Sci, 76, 921-8. https://doi.org/10.1111/j.1750-3841.2011.02282.x
  31. Lee SH, Cekanova M, Baek SJ (2008). Multiple mechanisms are involved in [6]-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Mol Carcinog, 47, 197-208. https://doi.org/10.1002/mc.20374
  32. Kim JS, Lee SI, Park HW, et al (2008). Cytotoxic components from the dried rhizomes of Zingiber officinale Rosc. Arch Pharmacol Res, 31, 415-8. https://doi.org/10.1007/s12272-001-1172-y
  33. Lee E, Surh YJ (1998). Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol. Cancer Lett, 134, 163-8. https://doi.org/10.1016/S0304-3835(98)00253-5
  34. Lee KW, Bode AM, Dong Z (2011). Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer, 11, 211-8. https://doi.org/10.1038/nrc3017
  35. Li X, Wang JN, Huang JM, et al (2011). Chrysin promotes tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced apoptosis in human cancer cell lines. Toxicol In Vitro, 25, 630-5. https://doi.org/10.1016/j.tiv.2010.12.013
  36. Longley DB, Harkin DP, Johnston PG (2003). 5-Fluorouracil: mechanism of action and clinical strategies. Nat Rev Cancer, 3, 330-8. https://doi.org/10.1038/nrc1074
  37. Majumdar AP, Banerjee S, Nautiyal J, et al (2009). Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr Cancer, 61, 544-53. https://doi.org/10.1080/01635580902752262
  38. Manju V, Nalini N (2005). Chemopreventive efficacy of ginger, a naturally occurring anticarcinogen during the initiation post-initiation stages of 1,2 dimethylhydrazine-induced colon cancer. Clin Chim Acta, 358, 60-7. https://doi.org/10.1016/j.cccn.2005.02.018
  39. Masuda Y, Kikuzaki H, Hisamoto M, Nakatani N (2004). Antioxidant properties of gingerol related compounds from ginger. Biofactors, 21, 293-6. https://doi.org/10.1002/biof.552210157
  40. Mayer RJ (2009). Targeted therapy for advanced colorectal cancer-more is not always better. N Engl J Med, 360, 623-5. https://doi.org/10.1056/NEJMe0809343
  41. Mehta RG, Murillo G, Naithani R, Peng X (2010). Cancer chemoprevetion by natural products: how far have we come? Pharmacol Res, 27, 950-61. https://doi.org/10.1007/s11095-010-0085-y
  42. Mohd Yusof YA, Shahriza ZA, Looi ML, et al (2008). Ginger extract (Zingiber officinale Roscoe) triggers apoptosis in hepatocarcinogenesis-induced rats. Med Health, 3, 263-74.
  43. Meregalli M, Martignoni G, Frontini L, et al (1998). Cancer doses of 5-fluorouracil and high-dose folinic acid in the treatment of metastatic colorectal cancer. Tumori, 84, 662-5.
  44. Miyoshi N, Nakamura Y, Ueda Y, et al (2003). Dietary ginger constituents, galanals A and B, are potent apoptosis inducers in human T lymphoma Jurkat cells. Cancer Lett, 199, 113-9. https://doi.org/10.1016/S0304-3835(03)00381-1
  45. Mohamed M, Sirajudeen K, Swamy M, et al (2010). Studies on the antioxidant properties of Tualang honey of Malaysia. Afr J Tradit Complement Altern Med, 7, 59-63. https://doi.org/10.1625/jcam.7.59
  46. Ng PL, Rajab NF, Then SM, et al (2014). Piper betle leaf extract enhances the cytotoxicity effect of 5-Fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells. J Zhejiang Univ-Sci B, [Epub ahead of print].
  47. Omar ZA, Ali ZM, Tamin NSI (2006). Malaysian cancer statistics. Data and figure: peninsular Malaysia 2006. National Cancer Registry, Ministry of Health Malaysia 2006.
  48. Pan MH, Hsieh MC, Kuo JM, et al (2008). 6-shogaol induces apoptosis in human colorectal carcinoma cells via ROS production , caspase activation, and GADD 153 expression. Mol Nutr Food Res, 52, 527-37. https://doi.org/10.1002/mnfr.200700157
  49. Rajamanickan S, Agarwal R (2008). Natural products and colon cancer: current status and future prospects. Drug Dev Res, 69, 460-71. https://doi.org/10.1002/ddr.20276
  50. Sang S, Hong J, Wu H, et al (2009). Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerol. J Agric Food Chem, 57, 10645-50. https://doi.org/10.1021/jf9027443
  51. 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
  52. Yodkeeree S, Sung B, Limtrakul P, Aggarwal BB (2009). Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: evidence for an essential role of reactive oxygen species. Cancer Res, 69, 6581-9. https://doi.org/10.1158/0008-5472.CAN-09-1161
  53. Tang XY, Zhu YQ, Tao WH, Wei B, Lin XL (2007). Synergistic effect of triptolide combined with 5-Fluorouracil on colon carcinoma. Postgrad Med J, 83, 338-43. https://doi.org/10.1136/pgmj.2006.055426
  54. Tong J, Xie G, He J, et al (2011). Synergistic antitumour effect of dichloroacetate in combination with 5-Fluorouracil in colorectal cancer. J Biomed Biotechnol, 2011, 740564.
  55. Wen CT, 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. Asian Pac J Cancer Prev, 13, 1605-10. https://doi.org/10.7314/APJCP.2012.13.4.1605
  56. Yogosawa SY, Yamada Y, Yasuda S, et al (2012). Dehydrozingerone, a structural analogue of curcumin, induces cell cycle arrest at the G2/M phase and accumulates intracellular ROS in HT-29 human colon cancer cells. J Nat Prod, 75, 2088-93. https://doi.org/10.1021/np300465f
  57. Zhu Y, Warin RF, Soroka DN, Chen H, Sang S (2013). Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: chemical synthesis and biological evaluation. PloS One, 8, 54677. https://doi.org/10.1371/journal.pone.0054677

Cited by

  1. Suppressive Effect of Sinomenine Combined with 5-Fluorouracil on Colon Carcinoma Cell Growth vol.15, pp.16, 2014, https://doi.org/10.7314/APJCP.2014.15.16.6737
  2. Effects of Two Traditional Chinese Cooking Oils, Canola and Pork, on pH and Cholic Acid Content of Faeces and Colon Tumorigenesis in Kunming Mice vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6225
  3. Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/β-catenin Pathways vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6549
  4. Anti-inflammatory and proapoptotic effects of umbelliferone in colon carcinogenesis vol.35, pp.10, 2016, https://doi.org/10.1177/0960327115618245
  5. Honey and its Phytochemicals: Plausible Agents in Combating Colon Cancer through its Diversified Actions vol.40, pp.4, 2016, https://doi.org/10.1111/jfbc.12239
  6. Chitosan-Coated Cinnamon/Oregano-Loaded Solid Lipid Nanoparticles to Augment 5-Fluorouracil Cytotoxicity for Colorectal Cancer: Extract Standardization, Nanoparticle Optimization, and Cytotoxicity Evaluation vol.65, pp.36, 2017, https://doi.org/10.1021/acs.jafc.7b03093
  7. 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