Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways

  • Khairunnisa’ Md YusofEmail author
  • Suzana Makpol
  • Lye Siew Fen
  • Rahman Jamal
  • Wan Zurinah Wan NgahEmail author
Original Paper


Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30–60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.


γ-Tocotrienol (γT3) 6-Gingerol (6G) SW837 human colorectal cancer cells Colon cancer Cell death RNA sequencing 



The research grant was supported by the Higher Institutions Centre of Excellence (HICoE; grant no: 106-64-01-005) from Ministry of Higher Education and The National University of Malaysia (UKM).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Nussbaumer S, Bonnabry P, Veuthey JL, Sandrine F (2011) Analysis of anticancer drugs: a review. Talanta 85:2265–2289CrossRefPubMedGoogle Scholar
  2. 2.
    Dropcho EJ (2011) The neurologic side effects of chemotherapeutic agents. Continuum (Minneap Minn) 17:95–112Google Scholar
  3. 3.
    Carroll RE, Benya RV, Turgeon DK et al (2011) Phase IIA clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila) 4(3):354–364CrossRefGoogle Scholar
  4. 4.
    Ryan JL, Heckler CE, Ling M et al (2013) Curcumin for radiation dermatitis: a randomized, double blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res 180(1):34–43CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tsao AS, Liu D, Martin J, Tang XM et al (2014) Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila) 2(11):931–941CrossRefGoogle Scholar
  6. 6.
    Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K (2011) Clinical trials of resveratrol. Ann N Y Acad Sci 1215:161–169CrossRefPubMedGoogle Scholar
  7. 7.
    Ho JW, Cheung MW (2014) Combination of phytochemicals as adjuvants for cancer therapy. Recent Pat Anticancer Drug Discov 9(3):297–302CrossRefPubMedGoogle Scholar
  8. 8.
    Lehar J, Krueger AS, Avery W et al (2009) Synergistic drug combination tend to improve therapeutically relevant selectively. Nat Biotechnol 27:659–666CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    de Kok TM, van Breda SG, Manson MM (2008) Mechanisms of combined action of different chemopreventive dietary compounds: a review. Eur J Nutr 47(Supp 2):51–59CrossRefPubMedGoogle Scholar
  10. 10.
    Yusof KM, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZW (2015) γ-Tocotrienol and 6-gingerol in combination synergistically induce cytotoxicity and apoptosis in HT-29 and SW837 human colorectal cancer cells. Molecules 20(6):10280–10297CrossRefPubMedGoogle Scholar
  11. 11.
    Kapoor V, Aggarwal S, Das SN (2016) 6-Gingerol mediates its anti tumor activities in human oral and cervical cancer cell lines through apoptosis and cell cycle arrest. Phytother Res 30:588–595CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang F, Zhang JG, Qu J, Zhang Q, Prasad C, Wei ZJ (2017) Assessment of anti-cancerous potential of 6-gingerol (Tongling White Ginger) and its synergy with drug on human cervical adenocarcinoma. Food Chem Toxicol 109:910–922CrossRefPubMedGoogle Scholar
  13. 13.
    Weng CJ, Wu CF, Huang HW, Ho CT, Yen GC (2010) Anti-invasion effects of 6-shogaol and 6-gingerol, two active components in ginger on human hepatocarcinoma cells. Mol Nutr Food Res 54:1618–1627CrossRefPubMedGoogle Scholar
  14. 14.
    Al-Abbasi FA, Alghamdi EA, Baghdadi MA, Alamoudi AJ et al (2016) Gingerol synergizes the cytotoxic effects of doxorubicin against liver cancer cells and protects from its vascular toxicity. Molecules 21(7):E886CrossRefPubMedGoogle Scholar
  15. 15.
    Abubakar IB, Lim KH, Kam TS, Loh HS (2017) Enhancement of apoptotic activities on brain cancer cells via combination of γ-tocotrienol and jerantinine. Phytomedicine 30:74–84CrossRefPubMedGoogle Scholar
  16. 16.
    Prasad S, Gupta SC, Tyagi AK, Aggarwal BB (2016) γ-Tocotrienol suppresses growth and sensitises human colorectal tumours to capecitabine in a nude mouse xenograft model by down-regulating multiple molecules. Br J Cancer 115(7):814–824CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Trapnell C, Roberts A, Goff L, Pertea G et al (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7(3):562–578CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Conesa A, Madrigal P, Tarazona S et al (2016) A survey of best practices for RNA-seq data analysis. Genome Biol 17(13):1–19Google Scholar
  19. 19.
    Kim EC, Min JK, Kim TY, Lee SJ, Yang HO, Han S, Kim YM et al (2005) [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo. Biochem Biophys Res Commun 335(2):300–308CrossRefPubMedGoogle Scholar
  20. 20.
    Wang CC, Chen LG, Lee LT, Yang LL (2003) Effects of 6-gingerol, an antioxidant from ginger, on inducing apoptosis in human leucemic HL-60 cells. Vivo 17(6):641–645Google Scholar
  21. 21.
    Funk JL, Frye JB, Oyarzo JN, Timmermann BN (2009) Comparative effects of two gingerol-containing Zingiber officinale extracts on experimental rheumatoid arthritis. J Nat Prod 72(3):403–407CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Weng CJ, Chou CP, Ho CT, Yen GC (2012) Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. Mol Nutr Food Res 56(8):1304–1314CrossRefPubMedGoogle Scholar
  23. 23.
    Poltronieri J, Becceneri AB, Fuzer AM, Filho JC, Martin AC, Cominetti MR et al (2014) [6]-gingerol as a cancer chemopreventive agent: a review of its activity on different steps of the metastatic process. Mini Rev Med Chem 14(4):313–321CrossRefPubMedGoogle Scholar
  24. 24.
    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(3):197–208CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P (2004) Toxic proteins released from mitochondria in cell death. Oncogene 23(16):2861–2874CrossRefPubMedGoogle Scholar
  26. 26.
    Shukla Y, Prasad S, Tripathi C, Singh M, George J, Kalra N (2007) In vitro and in vivo modulation of testosterone mediated alterations in apoptosis related proteins by [6]-gingerol. Mol Nutr Food Res 51(12):1492–1502CrossRefPubMedGoogle Scholar
  27. 27.
    Nakashima K, Virgona N, Miyazawa M, Watanabe T, Yano T (2010) The tocotrienol rich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells. Phytother Res 24(9):1317–1321CrossRefPubMedGoogle Scholar
  28. 28.
    Radhakrishnan AK, Mahalingam D, Selvaduraym KR, Nesaretnam K (2013) Supplementation with natural forms of vitamin E augments antigen-specific Th1-type immune response to tetanus toxoid. Biomed Res Int 2013:782067PubMedPubMedCentralGoogle Scholar
  29. 29.
    Myung SK, Ju W, Cho B, Oh SW, Park SM, Koo BK, Park BJ, Korean Meta-Analysis Study Group (2013) Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 346:f10CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Pierpaoli E, Viola V, Barucca A, Orlando F, Galli F, Provinciali M (2013) Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice. Carcinogenesis 34(6):1352–1360CrossRefPubMedGoogle Scholar
  31. 31.
    Sun W, Wang Q, Chen B, Liu J, Liu H, Xu W (2008) Gamma-tocotrienol-induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling. Br J Nutr 99(6):1247–1254CrossRefPubMedGoogle Scholar
  32. 32.
    Shirode AB, Sylvester PW (2010) Synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFκB signaling. Biomed Pharmacother 64(5):327–332CrossRefPubMedGoogle Scholar
  33. 33.
    Samant GV, Wali VB, Sylvester PW (2010) Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif 43(1):77–83CrossRefPubMedGoogle Scholar
  34. 34.
    Shirode AB, Sylvester PW (2011) Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment. J Bioanal Biomed 3:1–7CrossRefPubMedGoogle Scholar
  35. 35.
    Kannappan R, Gupta SC, Kim JH, Aggarwal BB (2012) Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes Nutr 7(1):43–52CrossRefPubMedGoogle Scholar
  36. 36.
    Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Crowley JJ et al (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301:39–51CrossRefPubMedGoogle Scholar
  37. 37.
    Comitato R, Leoni G, Canali R, Ambra R, Nesaretnam K, Virgili F (2010) Tocotrienols activity in MCF-7 breast cancer cells: involvement of ER-beta signal transduction. Mol Nutr Food Res 54(5):669–678CrossRefPubMedGoogle Scholar
  38. 38.
    Mahalingam D, Radhakrishnan AK, Amom Z, Ibrahim N, Nesaretnam K (2011) Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers. Eur J Clin Nutr 65(1):63–69CrossRefPubMedGoogle Scholar
  39. 39.
    Zhang JS, Li DM, Ma Y, He N, Gu Q, Wang FS, Jiang SQ et al (2013) γ-Tocotrienol induces paraptosis-like cell death in human colon carcinoma SW620 cells. PLoS One 8(2):e57779CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jiang Q (2014) Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy. Free Radic Biol Med 72C:76–90CrossRefGoogle Scholar
  41. 41.
    Siveen KS, Ahn KS, Ong TH, Shanmugam MK, Li F, Sethi G et al (2014) γ-Tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget 5(7):1897–1911CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Park YJ, Wen J, Bang S, Park SW, Song SY (2006) [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. Yonsei Med J 47(5):688–697CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Oyagbemi AA, Saba AB, Azeez OI (2010) Molecular targets of [6]-gingerol: its potential roles in cancer chemoprevention. BioFactors 36(3):169–178CrossRefPubMedGoogle Scholar
  44. 44.
    Hsieh TC, Elangovan S, Wu JM (2010) γ-Tocotrienol controls proliferation, modulates expression of cell cycle regulatory proteins and up-regulates quinone reductase NQO2 in MCF-7 breast cancer cells. Anticancer Res 30:2869–2874PubMedGoogle Scholar
  45. 45.
    Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M (2001) Tumor susceptibility of p21Waf1/Cip1- deficient mice. Cancer Res 61:6234–6238PubMedGoogle Scholar
  46. 46.
    Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ (1998) The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396:177–180CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pateras IS, Apostolopoulou K, Niforou K, Kotsinas A, Gorgoulis VG (2009) p57KIP2: “Kip”ing the cell under control. Mol Cancer Res 7(12):1902–1919CrossRefPubMedGoogle Scholar
  48. 48.
    Hashimoto Y, Kohri K, Kaneko Y, Morisaki H, Kato T, Ikeda K, Nakanishi M (1998) Critical role for the 310 helix region of p57 (Kip2) in cyclin-dependent kinase 2 inhibition and growth suppression. J Biol Chem 273(26):16544–16550CrossRefPubMedGoogle Scholar
  49. 49.
    Zhao H, Jin S, Antinore MJ, Lung FD, Fan F, Blanck P, Zhan Q et al (2000) The central region of Gadd45 is required for its interaction with p21/WAF1. Exp Cell Res 258(1):92–100CrossRefPubMedGoogle Scholar
  50. 50.
    Chang Q, Bhatia D, Zhang Y, Meighan T, Castranova V, Shi X, Chen F (2007) Incorporation of aninternal ribosome entry site-dependent mechanism in arsenic-induced GADD45 alpha expression. Cancer Res 67:6146–6154CrossRefPubMedGoogle Scholar
  51. 51.
    Salvador JM, Brown-Clay JD, Fornace AJ (2013) Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv Exp Med Biol 793:1–19CrossRefPubMedGoogle Scholar
  52. 52.
    Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA (2000) Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control. J Biol Chem 275(22):16810–16819CrossRefPubMedGoogle Scholar
  53. 53.
    Yang C, Yang S, Wood KB, Hornicek FJ, Schwab JH, Fondren G, Mankin H, Duan Z (2009) Multidrug resistant osteosarcoma cell lines exhibit deficiency of GADD45alpha expression. Apoptosis 14(1):124–133CrossRefPubMedGoogle Scholar
  54. 54.
    Gao M, Guo N, Huang C, Song L (2009) Diverse roles of GADD45alpha in stress signaling. Curr Protein Pept Sci 10:388–394CrossRefPubMedGoogle Scholar
  55. 55.
    Paruthiyil S, Cvoro A, Tagliaferri M, Cohen I, Shtivelman E, Leitman DC (2011) Estrogen receptor beta causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclinB1, GADD45A, and BTG2. Breast Cancer Res Treat 129(3):777–784CrossRefPubMedGoogle Scholar
  56. 56.
    Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE (2011) FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress. J Biol Chem 286:7468–7478CrossRefPubMedGoogle Scholar
  57. 57.
    Song L, Li J, Zhang D, Liu ZG, Ye J, Zhan Q, Shen HM, Whiteman M, Huang C (2006) IKKbeta programs to turn on the GADD45alpha-MKK4-JNK apoptotic cascade specifically via p50 NF-kappaB in arsenite response. J Cell Biol 175:607–617CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Yoshida T, Maeda A, Horinaka M, Shiraishi T, Nakata S, Wakada M, Yogosawa S, Sakai T (2005) Quercetin induces gadd45 expression through a p53-independent pathway. Oncol Rep 14(5):1299–1303PubMedGoogle Scholar
  59. 59.
    Wang XW, Zhan Q, Coursen JD, Khan MA, Yu L, Hollander MC, Harris CC et al (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96(7):3706–3711CrossRefPubMedGoogle Scholar
  60. 60.
    Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, Taniguchi N, Huang XL, Goldring MB (2005) A novel role for GADD45beta as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem 280:38544–38555CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Saha A, Kuzuhara T, Echigo N, Fujii A, Suganuma M, Fujiki H (2010) Apoptosis of human lung cancer cells by curcumin mediated through up-regulation of “growth arrest and DNA damage inducible genes 45 and 153. Biol Pharm Bull 33(8):1291–1299CrossRefPubMedGoogle Scholar
  62. 62.
    Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Costa RH et al (2005) Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol 25(24):10875–10894CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Raychaudhuri P, Park HJ (2011) FoxM1: a master regulator of tumor metastasis. Cancer Res 71(13):4329–4333CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Wonsey DR, Follettie MT (2005) Loss of the forkhead transcription factor FOXM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 65(12):5181–5189CrossRefPubMedGoogle Scholar
  65. 65.
    Bektas N, Haaf A, Veeck J, Wild PJ, Lüscher-Firzlaff J, Hartmann A, Knuchel R, Dahl E (2008) Tight correlation between expression of the Forkhead transcription factor FOXM1 and HER2 in human breast cancer. BMC Cancer 8:42–50CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    van den Boom J, Wolter M, Kuick R, Misek DE, Youkilis AS, Wechsler DS, Hanash SM et al (2003) Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol 163(3):1033–1043CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Huang S et al (2006) FOXM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res 66(7):3593–3602CrossRefPubMedGoogle Scholar
  68. 68.
    Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, Petersen I et al (2001) Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA 98(24):13784–13789CrossRefPubMedGoogle Scholar
  69. 69.
    Romagnoli S, Fasoli E, Vaira V, Falleni M, Pellegrini C, Catania A, Bosari S et al (2009) Identification of potential therapeutic targets in malignant mesothelioma using cell-cycle gene expression analysis. Am J Pathol 174(3):762–770CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Loric S et al (2006) Sonic Hedgehog dependent proliferation in a series of patients with colorectal cancer. Surgery 139(5):665–670CrossRefPubMedGoogle Scholar
  71. 71.
    Radhakrishnan SK, Gartel AL (2008) FOXM1: the Achilles’ heel of cancer? Nat Rev Cancer 8(3):c1CrossRefPubMedGoogle Scholar
  72. 72.
    Karadedou CT, Gomes AR, Chen J, Petkovic M, Zwolinska AK, Feltes A, Lam EW et al (2012) FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer. Oncogene 31:1845–1858CrossRefPubMedGoogle Scholar
  73. 73.
    Francis RE, Myatt SS, Krol J, Hartman J, Peck B, Lam EW et al (2009) FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer. Int J Oncol 35:57–68PubMedPubMedCentralGoogle Scholar
  74. 74.
    McGovern UB, Francis RE, Peck B, Guest SK, Wang J, Lam EW et al (2009) Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol Cancer Ther 8:582–591CrossRefPubMedGoogle Scholar
  75. 75.
    Fernandez de Mattos S, Villalonga P, Clardy J, Lam EW (2008) FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther 7:3237–3246CrossRefPubMedGoogle Scholar
  76. 76.
    Kalinichenko VV, Major ML, Wang X, Petrovic V, Yoder HM, Costa RH et al (2004) Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev 18(7):830–850CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Katoh M (2007) Networking of WNT, FGF, Notch, BMP, and hedgehog signaling pathways during carcinogenesis. Stem Cell Rev 3(1):30–38CrossRefPubMedGoogle Scholar
  78. 78.
    Sarkar FH, Li Y, Wang Z, Kong D (2010) The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metastasis Rev 29(3):383–394CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P, Thesleff I, Pirinen S, Nieminen P (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 74(5):1043–1050CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275(5307):1787–1790CrossRefPubMedGoogle Scholar
  81. 81.
    Xu W, Du M, Zhao Y, Wang Q, Sun W, Chen B (2012) γ-Tocotrienol inhibits cell viability through suppression of β-catenin/Tcf signaling in human colon carcinoma HT-29 cells. J Nutr Biochem 23(7):800–807CrossRefPubMedGoogle Scholar
  82. 82.
    Wang M, Kaufman RJ (2014) The impact of the endoplasmic reticulum protein folding environment on cancer development. Nat Rev Cancer 14:581–597CrossRefPubMedGoogle Scholar
  83. 83.
    Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13(2):89–102CrossRefPubMedGoogle Scholar
  84. 84.
    Harding HP, Zahng Y, Zeng H, Novoa I, Ron D et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11(3):619–633CrossRefPubMedGoogle Scholar
  85. 85.
    Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ (1999) Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J 339(1):135–141PubMedPubMedCentralGoogle Scholar
  86. 86.
    Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415(6867):92–96CrossRefPubMedGoogle Scholar
  87. 87.
    Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107(7):881–891CrossRefPubMedGoogle Scholar
  88. 88.
    Nishitoh H, Matsuzawa A, Tobiume K, Saeguda K, Takeda K, Inoue K, Ichijo H et al (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16(11):1345–1355CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Ishikawa T, Watanabe N, Nagano M, Kawai-Yamada M, Lam E (2011) Bax inhibitor-1: a highly conserved endoplasmic reticulum-resident cell death suppressor. Cell Death Differ 18(8):1271–1278CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Sano R, Reed JC (2013) ER stress induced cell death mechanisms. Biochim Biophys Acta 1833(12):3460–3470CrossRefPubMedGoogle Scholar
  91. 91.
    Park SK, Sanders BG, Kline K (2010) Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 124(2):361–375CrossRefPubMedGoogle Scholar
  92. 92.
    Patacsil D, Tran AT, Cho YS, Suy S, Saenz F, Malyukova I, Kumar D et al (2012) Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells. J Nutr Biochem 23(1):93–100CrossRefPubMedGoogle Scholar
  93. 93.
    Tiwari RV, Parajuli P, Sylvester PW (2015) γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death. Biochem Cell Biol 93(4):306–320CrossRefPubMedGoogle Scholar
  94. 94.
    Comamito R, Guantario B, Leoni G, Nasaretnam K, Ronci MB, Canali R, Virgili F (2016) Tocotrienols induce endoplasmic reticulum stress and apoptosis in cervical cancer cells. Genes Nutr 11:32CrossRefGoogle Scholar
  95. 95.
    Constantinou C, Hyatt JA, Vraka PS, Papas A, Papas KA, Constantinou AI et al (2009) Induction of caspase-independent programmed cell death by vitamin E natural homologs and synthetic derivatives. Nutr Cancer 61(6):864–874CrossRefPubMedGoogle Scholar
  96. 96.
    Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL (2008) Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signaling pathways. Br J Cancer 99(11):1832–1841CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Nigam N, George J, Srivastava S, Roy P, Bhui K, Singh M, Shukla Y (2010) Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signalling pathway in B[a]-p-induced mouse skin tumorigenesis. Cancer Chemother Pharmacol 65(4):687–696CrossRefPubMedGoogle Scholar
  98. 98.
    Radhakrishnan EK, Bava SV, Narayanan SS, Nath LR, Thulasidasan AK, Soniya EV, Anto TJ (2014) [6]-Gingerol induces caspase dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling. PLoS One 9(8):e104401CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Chakraborty D, Bishayee K, Ghosh S, Biswas R, Mandal SK, Khuda-Bukhsh AR (2013) [6]-Gingerol induces caspase 3 dependent apoptosis and autophagy in cancer cells: drug DNA interaction and expression of certain signal genes in HeLa cells. Eur J Pharmacol 694(1–3):20–29Google Scholar
  100. 100.
    Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T et al (2005) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165(3):347–356CrossRefGoogle Scholar
  101. 101.
    Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789CrossRefPubMedGoogle Scholar
  102. 102.
    Maurel M, McGrath EP, Mnich K, Healy S, Chevet E, Samali A (2015) Controlling the unfolded protein response-mediated life and death decisions in cancer. Semin Cancer Biol 33:57–66CrossRefPubMedGoogle Scholar
  103. 103.
    Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial divison. Science 334(6054):358–362CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Hatch AL, Gurel PS, Higgs HN (2014) Novel roles for actin in mitochondrial fission. J Cell Sci 127:4549–4560CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Hoppins S, Nunnari J (2012) Mitochondrial dynamics and apoptosis-the ER connection. Science 337(6098):1052–1054CrossRefPubMedGoogle Scholar
  106. 106.
    Malhotra JD, Kaufman RJ (2011) ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb Perspect Biol 3(9):a004424CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Li J, Lee B, Lee AS (2006) Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 281(11):7620–7670CrossRefGoogle Scholar
  108. 108.
    Zou CG, Cao XZ, Zhao YS, Gao SY, Li SD, Liu XY, Zhang Y, Zhang KQ (2008) The molecular mechanism of endoplasmic reticulum stress-induced apoptosis in PC-12 neuronal cells: the protective effect of insulin-like growth factor-1. Endocrinology 150(1):277–285CrossRefPubMedGoogle Scholar
  109. 109.
    Berti M, Vindigni A (2016) Replication stress: getting back on track. Nat Struct Mol Biol 23(2):103–109CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Dobblestein M, Sorensen CS (2015) Exploiting replicative stress to treat cancer. Nat Rev Drug Dis 14(6):405–423CrossRefGoogle Scholar
  111. 111.
    Puigvert JC, Sanjiv K, Helleday T (2016) Targeting DNA repair, DNA metabolism and replication stress as anti-cancer strategies. FEBS J 283(2):232–245CrossRefPubMedGoogle Scholar
  112. 112.
    De Lorenzo SB, Patel AG, Hurley RM, Kaufmann SH (2013) The elephant and the blind men: making sense of PARP inhibitors in homologous recombination deficient tumor cells. Front Oncol 3:228CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Dong L, Wang H, Niu J, Zou M, Wu N, Wu N, Zou Z et al (2015) Echinacoside induces apoptotic cancer cell death by inhibiting the nucleotide pool sanitizing enzyme MTH1. Onco Targets Ther 8:3649–3664PubMedPubMedCentralGoogle Scholar
  114. 114.
    Kig C, Beullens M, Beke L, Van Eynde A, Linders JT, Brehmer D, Bollen M (2017) Maternal embryonic leucine zipper kinase (MELK) reduces replication stress in glioblastoma cells. J Biol Chem 292(31):12786CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Joshi K, Banasavadi-Siddegowda Y, Mo X, Kim SH, Mao P, Nardini D, Nakano I et al (2013) MELK-dependent FOXM! Phosphorylation is essential for proliferation of glioma stem cells. Stem Cells 31(6):1051–1063CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Minata M, Gu C, Joshi K, Nakano-Okuno M, Hong C, Nakano I et al (2014) Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition. PLoS One 9(4):e92546CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Long DT, Raschle M, Joukov V, Walter JC (2011) Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science 333(6038):84–87CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Sung P, Klein H (2006) Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7:739–750CrossRefPubMedGoogle Scholar
  119. 119.
    Wu MH, Lin LC, Lee TC (2016) Augmentation of response to therapeutic agents by (−)-gallocatechin-gallate through inhibition of RAD51 nuclear translocation. Exp Mol Ther 76(14):3733Google Scholar

Copyright information

© The Japanese Society of Pharmacognosy 2019

Authors and Affiliations

  1. 1.UKM Medical Molecular Biology Institute (UMBI)UKM Medical CenterKuala LumpurMalaysia
  2. 2.Department of Biochemistry, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  3. 3.BioEasy Sdn. BhdShah AlamMalaysia

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