Top

Published in:

01-04-2020 | Review

Vitamin E and cancer: an update on the emerging role of γ and δ tocotrienols

Authors: Constantina Constantinou, Christiana Charalambous, Dimitrios Kanakis

Published in: European Journal of Nutrition | Issue 3/2020

Abstract

Despite significant advances in the diagnosis and treatment of cancer, the latter still remains a fatal disease due to the lack of prevention, early diagnosis, and effective drugs. Radiotherapy, chemotherapy, and surgery are not only expensive but produce a number of side effects that are detrimental to the patients’ quality of life. Therefore, there is a great need to discover anti-cancer therapies that are specific to cancer cells and affordable, safe, and well tolerated by the patients. Vitamin E is a potential candidate due to its safety. Accumulating evidence on the anti-cancer potency of vitamin E has shifted the focus from tocopherols (TOCs) to tocotrienols (TTs). γ-TT and δ-TT have the highest anti-cancer activities and target common molecular pathways involved in the inhibition of the cell cycle, the induction of apoptosis and autophagy, and the inhibition of invasion, metastasis, and angiogenesis. Future directions should focus on further investigating how γ-TT and δ-TT (solely or in combination) induce anti-cancer molecular pathways when used in the presence of conventional chemotherapeutic drugs. These studies should be carried out in vitro, and promising results and combinations should then be assessed in in vivo experiments and finally in clinical trials. Finally, future research should focus on further evaluating the roles of γ-TT and δ-TT in the chemoprevention of cancer.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210 CrossRefPubMed

Sailo BL, Banik K, Padmavathi G, Javadi M, Bordoloi D, Kunnumakkara AB (2018) Tocotrienols: the promising analogues of vitamin E for cancer therapeutics. Pharmacol Res 130:259–272. https://doi.org/10.1016/j.phrs.2018.02.017 CrossRefPubMed

Ling MT, Luk SU, Al-Ejeh F, Khanna KK (2012) Tocotrienol as a potential anticancer agent. Carcinogenesis 33(2):233–239. https://doi.org/10.1093/carcin/bgr261 CrossRefPubMed

Kanchi MM, Rane G, Kumar AP, Shanmugam MK, Sethi G (2017) Tocotrienols: the unsaturated sidekick shifting new paradigms in vitamin E therapeutics. Drug Discov Today 22(12):1765–1781. https://doi.org/10.1016/j.drudis.2017.08.001 CrossRefPubMed

Evans HM, Bishop KS (1922) On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science 56(1458):650–651PubMed

Peh HY, Tan WSD, Liao W, Wong WSF (2016) Associate Editor: Y. Zhang: vitamin E therapy beyond cancer: tocopherol versus tocotrienol. Pharmacol Ther 162:152–169. https://doi.org/10.1016/j.pharmthera.2015.12.003 CrossRefPubMed

Mizushina Y, Nakagawa K, Shibata A, Awata Y, Kuriyama I, Shimazaki N, Koiwai O, Uchiyama Y, Sakaguchi K, Miyazawa T, Yoshida H (2006) Inhibitory effect of tocotrienol on eukaryotic DNA polymerase lambda and angiogenesis. Biochem Biophys Res Commun 339(3):949–955PubMed

Khan MR, Siddiqui S, Parveen K, Javed S, Diwakar S, Siddiqui WA (2010) Nephroprotective action of tocotrienol-rich fraction (TRF) from palm oil against potassium dichromate (K 2 Cr 2 O 7)-induced acute renal injury in rats. Chem Biol Interact 186(2):228–238. https://doi.org/10.1016/j.cbi.2010.04.025 CrossRefPubMed

Sen CK, Rink C, Khanna S (2010) Palm oil–derived natural vitamin E α-tocotrienol in brain health and disease. J Am Coll Nutr 29(sup3):314S–323SPubMedPubMedCentral

10.

Hosomi A, Arita M, Sato Y, Arai H, Inoue K, Kiyose C, Igarashi O, Ueda T (1997) Affinity for a-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett 409(1):105–108. https://doi.org/10.1016/S0014-5793(97)00499-7 CrossRefPubMed

11.

Birringer M, Pfluger P, Kluth D, Landes N, Brigelius-Flohé R (2002) Identities and differences in the metabolism of tocotrienols and tocopherols in HepG2 cells. J Nutr 132(10):3113–3118PubMed

12.

Ahsan H, Ahad A, Iqbal J, Siddiqui WA (2014) Pharmacological potential of tocotrienols: a review. Nutr Metab 11(1):52. https://doi.org/10.1186/1743-7075-11-52 CrossRef

13.

Abdul-Majeed S, Mohamed N, Soelaiman I (2013) A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis. Curr Drug Targets 14(13):1579–1590PubMed

14.

Abdul-Majeed S, Mohamed N, Soelaiman I (2015) The use of delta-tocotrienol and lovastatin for anti-osteoporotic therapy. Life Sci 125:42–48PubMed

15.

Wada S (2012) Cancer preventive effects of vitamin E. Curr Pharm Biotechnol 13(1):156–164PubMed

16.

Jiang Q (2017) Natural forms of vitamin E as effective agents for cancer prevention and therapy. Adv. Nutr. 8:850–867PubMedPubMedCentral

17.

Jiang Q (2018) Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms. IUBMB Life. https://doi.org/10.1002/iub.1978 CrossRefPubMed

18.

Montagnani Marelli M, Marzagalli M, Fontana F, Raimondi M, Moretti RM, Limonta P (2019) Anticancer properties of tocotrienols: a review of cellular mechanisms and molecular targets. J Cell Physiol 234:1147–1164PubMed

19.

Abu-Fayyad A, Kamal MM, Nazzal S, Carroll JL, Dragoi A-M, Cody R, Cardelli J (2018) Development and in vitro characterization of nanoemulsions loaded with paclitaxel/γ-tocotrienol lipid conjugates. Int J Pharm 536(1):146–157. https://doi.org/10.1016/j.ijpharm.2017.11.062 CrossRefPubMed

20.

Srivastava JK, Gupta S (2006) Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochem Biophys Res Commun 346(2):447–453PubMed

21.

Yap WN, Chang PN, Han HY, Lee DTW, Ling MT, Wong YC, Yap YL (2008) Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer 99(11):1832–1841. https://doi.org/10.1038/sj.bjc.6604763 CrossRefPubMedPubMedCentral

22.

Yap WN, Zaiden N, Tan YL, Ngoh CP, Zhang XW, Wong YC, Ling MT, Yap YL (2010) Id1, inhibitor of differentiation, is a key protein mediating anti-tumor responses of gamma-tocotrienol in breast cancer cells. Cancer Lett 291(2):187–199. https://doi.org/10.1016/j.canlet.2009.10.012 CrossRefPubMed

23.

Aggarwal BB, Sundaram C, Prasad S, Kannappan R (2010) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80(11):1613–1631. https://doi.org/10.1016/j.bcp.2010.07.043 CrossRefPubMedPubMedCentral

24.

Kannappan R, Ravindran J, Prasad S, Sung B, Yadav VR, Reuter S, Chaturvedi MM, Aggarwal BB (2010) Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors. Mol Cancer Ther 9(8):2196–2207. https://doi.org/10.1158/1535-7163.MCT-10-0277 CrossRefPubMed

25.

Cardenas E, Ghosh R (2013) Vitamin E: a dark horse at the crossroad of cancer management. Biochem Pharmacol 86(7):845–852. https://doi.org/10.1016/j.bcp.2013.07.018 CrossRefPubMedPubMedCentral

26.

Sun W, Xu W, Liu H, Liu J, Wang Q, Zhou J, Dong F, Chen B (2009) γ-Tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 20:276–284PubMed

27.

Wang C, Husain K, Zhang A, Centeno BA, Chen DT, Tong Z, Sebti SM, Malafa MP (2015) EGR-1/Bax pathway plays a role in vitamin E δ-tocotrienol-induced apoptosis in pancreatic cancer cells. J Nutr Biochem 26:797–807PubMedPubMedCentral

28.

Wada S (2009) Chemoprevention of tocotrienols: the mechanism of antiproliferative effects. Forum Nutr 61:204–216. https://doi.org/10.1159/000212752 CrossRefPubMed

29.

Galli F, Azzi A (2010) Present trends in vitamin E research. BioFactors 36(1):33–42. https://doi.org/10.1002/biof.75 CrossRefPubMed

30.

Catalgol B, Batirel S, Ozer NK (2011) Cellular protection and therapeutic potential of tocotrienols. Curr Pharm Des 17(21):2215–2220PubMed

31.

Kannappan R, Gupta SC, Kim JH, Aggarwal BB (2012) Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes Nutr 7(1):43–52. https://doi.org/10.1007/s12263-011-0220-3 CrossRefPubMed

32.

De Silva L, Chuah LH, Meganathan P, Fu J-Y (2016) Tocotrienol and cancer metastasis. BioFactors 42(2):149–162. https://doi.org/10.1002/biof.1259 CrossRefPubMed

33.

Hsieh T, Wu JM (2008) Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and γ-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol 33(4):851–859PubMed

34.

Samant G, Wali V, Sylvester P (2010) Anti-proliferative effects of γ-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif 43(1):77–83PubMed

35.

Wada S, Satomi Y, Murakoshi M, Noguchi N, Yoshikawa T, Nishino H (2005) Carcinogenesis and cancer prevention: tumor suppressive effects of tocotrienol in vivo and in vitro. Cancer Lett 229:181–191. https://doi.org/10.1016/j.canlet.2005.06.036 CrossRefPubMed

36.

Wu S, Ng L (2010) Tocotrienols inhibited growth and induced apoptosis in human HeLa cells through the cell cycle signaling pathway. Integr Cancer Ther 9(1):66–72. https://doi.org/10.1177/1534735409357757 CrossRefPubMed

37.

Huang Y, Wu R, Su Z, Guo Y, Zheng X, Yang CS, Kong A (2017) A naturally occurring mixture of tocotrienols inhibits the growth of human prostate tumor, associated with epigenetic modifications of cyclin-dependent kinase inhibitors p21 and p27. J Nutr Biochem 40:155–163. https://doi.org/10.1016/j.jnutbio.2016.10.019 CrossRefPubMed

38.

Fernandes NV, Guntipalli PK, Mo H (2010) d-δ-Tocotrienol-mediated cell cycle arrest and apoptosis in human melanoma cells. Anticancer Res 30(12):4937–4944PubMed

39.

Ji X, Heamanu A, Goja A, Gupta SV, Wang Z, Sarkar FH (2012) Delta-tocotrienol suppresses Notch-1 pathway by upregulating miR-34a in nonsmall cell lung cancer cells. Int J Cancer 131(11):2668–2677PubMedPubMedCentral

40.

Hodul PJ, Dong Y, Husain K, Pimiento JM, Chen J, Zhang A, Francois R, Pledger WJ, Coppola D, Sebti SM, Chen D, Malafa MP (2013) Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism. PLoS One 8(2):e52526. https://doi.org/10.1371/journal.pone.0052526 CrossRefPubMedPubMedCentral

41.

Ye C, Zhao W, Li M, Zhuang J, Yan X, Lu Q, Chang C, Huang X, Zhou J, Xie B, Zhang Z, Yao X, Yan J, Guo H (2015) δ-Tocotrienol induces human bladder cancer cell growth arrest, apoptosis and chemosensitization through inhibition of STAT3 pathway. PLoS One 10(4):e0122712. https://doi.org/10.1371/journal.po CrossRefPubMedPubMedCentral

42.

Shibata A, Nakagawa K, Tsuduki T, Miyazawa T (2015) Research Article: δ-Tocotrienol treatment is more effective against hypoxic tumor cells than normoxic cells: potential implications for cancer therapy. J Nutr Biochem 26:832–840. https://doi.org/10.1016/j.jnutbio.2015.02.011 CrossRefPubMed

43.

Atia A, Abdullah A (2013) Tocotrienols: molecular aspects beyond its antioxidant activity. JMRP 2:246–250

44.

Degterev A, Boyce M, Yuan J (2003) A decade of caspases. Oncogene 22(53):8543PubMed

45.

Constantinou C, Papas K, Constantinou A (2009) Caspase-independent pathways of programmed cell death: the unraveling of new targets of cancer therapy? Curr Cancer Drug Targets 9(6):717–728PubMed

46.

Hengartner MO (2000) The biochemistry of apoptosis. Nature 407(6805):770PubMed

47.

Wali VB, Bachawal SV, Sylvester PW (2009) ‘Endoplasmic reticulum stress mediates c-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis 14:1366–1377PubMed

48.

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 signalling. Breast Cancer Res Treat 124:361–375PubMed

49.

Patacsil D, Tran AT, Cho YS, Suy S, Saenza F, Malyukovaa I, Ressomb H, Collins SP, Clarke P, Kumar D (2012) Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells. J Nutr Biochem 23:93–100PubMed

50.

Tiwari RV, Parajuli P, Sylvester PW (2014) γ-Tocotrienol-induced autophagy in malignant mammary cancer cells. Exp Biol Med 239:33–44

51.

Tiwari RV, Parajuli P, Sylvester PW (2015) Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death. Biochem Cell Biol 93:306–320PubMed

52.

Comitato R, Guantario B, Leoni G, Nesaretnam K, Ronci MB, Canali R, Virgili F (2016) Tocotrienols induce endoplasmic reticulum stress and apoptosis in cervical cancer cells. Genes Nutr 11:32PubMedPubMedCentral

53.

Montagnani Marelli M, Marzagalli M, Moretti RM, Beretta G, Casati L, Comitato R, Gravina GL, Festuccia C, Patrizia Limonta (2016) Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress mediated apoptosis in human melanoma cells. Sci Rep 6:30502PubMedPubMedCentral

54.

Sylvester WP, Ayoub MN (2013) Tocotrienols target PI3K/Akt signaling in anti-breast cancer therapy. Anticancer Agents Med Chem 13(7):1039–1047PubMed

55.

McIntyre BS, Briski KP, Gapor A, Sylvester PW (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells (44544). Proc Soc Exp Biol Med 224(4):292–301PubMed

56.

Shah S, Sylvester PW (2004) Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary epithelial cells. Exp Biol Med 229(8):745–755

57.

Shun M, Yu W, Gapor A, Parsons R, Atkinson J, Sanders BG, Kline K (2004) Pro-apoptotic mechanisms of action of a novel vitamin E analog (α-TEA) and a naturally occurring form of vitamin E (δ-tocotrienol) in MDA-MB-435 human breast cancer cells. Nutr Cancer 48(1):95–105PubMed

58.

Loganathan R, Selvaduray KR, Nesaretnam K, Radhakrishnan AK (2013) Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity. Cell Prolif 46(2):203–213. https://doi.org/10.1111/cpr.12014 CrossRefPubMedPubMedCentral

59.

Comitato R, Leoni G, Canali R, Ambra R, Nesaretnam K, Virgili F (2010) Tocotrienols activity in MCF-7 breast cancer cells: involvement of ERβ signal transduction. Mol Nutr Food Res 54(5):669–678PubMed

60.

Khallouki F, Caze-Subra S, Bystricky K, Balaguer P, Poirot M, Silvente-Poirot S (2016) Molecular and biochemical analysis of the estrogenic and proliferative properties of vitamin E compounds. Front Oncol 5:287PubMedPubMedCentral

61.

Agarwal MK, Agarwal ML, Athar M, Gupta S (2004) Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle 3(2):205–211PubMed

62.

Xu W, Liu J, Liu H, Qi G, Sun X, Sun W, Chen B (2009) Inhibition of proliferation and induction of apoptosis by γ-tocotrienol in human colon carcinoma HT-29 cells. Nutrition 25(5):555–566. https://doi.org/10.1016/j.nut.2008.10.019 CrossRefPubMed

63.

Ahn KS, Sethi G, Krishnan K, Aggarwal BB (2007) Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 282(1):809–820PubMed

64.

Inoue A, Takitani K, Koh M, Kawakami C, Kuno T, Tamai H (2011) Induction of apoptosis by γ-tocotrienol in human cancer cell lines and leukemic blasts from patients: dependency on bid, cytochrome c, and caspase pathway. Nutr Cancer 63(5):763–770. https://doi.org/10.1080/01635581.2011.563030 CrossRefPubMed

65.

Wilankar C, Khan NM, Checker R, Sharma D, Patwardhan R, Gota V, Sandur SK, Devasagayam T (2011) γ-Tocotrienol induces apoptosis in human T cell lymphoma through activation of both intrinsic and extrinsic pathways. Curr Pharm Design 17(21):2176–2218

66.

Rajendran P, Li F, Manu KA, Shanmugam MK, Loo SY, Kumar AP, Sethi G (2011) γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent. Br J Pharmacol 163(2):283–298. https://doi.org/10.1111/j.1476-5381.2010.01187.x CrossRefPubMedPubMedCentral

67.

Sakai M, Okabe M, Tachibana H, Yamada K (2006) Research article: apoptosis induction by γ-tocotrienol in human hepatoma Hep3B cells. J Nutr Biochem 17:672–676. https://doi.org/10.1016/j.jnutbio.2005.11.001 CrossRefPubMed

68.

Lim S, Loh H, Ting K, Bradshaw TD, Zeenathul NA (2014) Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells. BMC Complement Altern Med 14:469. https://doi.org/10.1186/1472-6882-14-469 CrossRefPubMedPubMedCentral

69.

Hussein D, Mo H (2009) d-δ-Tocotrienol-mediated suppression of proliferation of human PANC-1, MIA PaCA-2 and Bx-PC3 pancreatic carcinoma cells. Pancreas 38(4):e124–e136PubMed

70.

Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. https://doi.org/10.1038/35052073 CrossRefPubMed

71.

Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354PubMed

72.

Appert-Collin A, Hubert P, Crémel G, Bennasroune A (2015) Role of ErbB receptors in cancer cell migration and invasion. Front Pharmacol 6:283. https://doi.org/10.3389/fphar.2015.00283 CrossRefPubMedPubMedCentral

73.

Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E (2014) PI3K/AKT signaling pathway and cancer: an updated review. Ann Med 46(6):372–383PubMed

74.

Shah S, Gapor A, Sylvester PW (2003) Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. Nutr Cancer 45(2):236–246PubMed

75.

Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, Stone W, Campbell S, Reddy SAG, Krishnan K (2011) Original contribution: tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radical Biol Med 51:1164–1174. https://doi.org/10.1016/j.freeradbiomed.2011.06.008 CrossRef

76.

Alawin OA, Ahmed RA, Dronamraju V, Briski KP, Sylvester PW (2017) γ-Tocotrienol-induced disruption of lipid rafts in human breast cancer cells is associated with a reduction in exosome heregulin content. J Nutr Biochem 48:83–93PubMed

77.

Jang Y, Rao X, Jiang Q (2017) Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment. J Nutr Biochem 46:49–56PubMedPubMedCentral

78.

Yang C, Jiang Q (2019) Vitamin E δ-tocotrienol inhibits TNF-α-stimulated NF-κB activation by up-regulation of anti-inflammatory A20 via modulation of sphingolipid including elevation of intracellular dihydroceramides. J Nutr Biochem 64:101–109PubMed

79.

Parajuli P, Tiwari R, Sylvester P (2015) Anti-proliferative effects of γ-tocotrienol are associated with suppression of c-Myc expression in mammary tumour cells. Cell Prolif 48(4):421–435PubMedPubMedCentral

80.

Chang PN, Yap WN, Lee DTW, Ling MT, Wong YC, Yap YL (2009) Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. Nutr Cancer 61(3):357–366. https://doi.org/10.1080/01635580802567166 CrossRefPubMed

81.

Dolcet X, Llobet D, Pallares J, Matias-Guiu X (2005) NF-kB in development and progression of human cancer. Virchows Arch 446(5):475–482PubMed

82.

Chai EZP, Shanmugam MK, Arfuso F, Dharmarajan A, Wang C, Kumar AP, Samy RP, Lim LH, Wang L, Goh BC (2016) Targeting transcription factor STAT3 for cancer prevention and therapy. Pharmacol Ther 162:86–97PubMed

83.

Bachawal SV, Wali VB, Sylvester PW (2010) Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res 30(2):429–437PubMed

84.

Constantinou C, Hyatt JA, Vraka PS, Papas A, Papas KA, Neophytou C, Hadjivassiliou V, Constantinou AI (2009) Induction of caspase-independent programmed cell death by vitamin E natural homologs and synthetic derivatives. Nutr Cancer 61(6):864–874PubMed

85.

Constantinou C, Neophytou C, Vraka P, Hyatt J, Papas K, Constantinou A (2012) Induction of DNA damage and caspase-independent programmed cell death by vitamin E. Nutr Cancer 64(1):136–152PubMed

86.

Sperandio S, de Belle I, Bredesen DE (2000) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 97:14376–14381PubMed

87.

Zhang J-S, Li D-M, He N, Liu Y-H, Wang C-H, Jiang SQ, Chen B-Q, Liu J-R (2011) A paraptosis-like cell death induced by δ-tocotrienol in human colon carcinoma SW620 cells is associated with the suppression of the Wnt signaling pathway. Toxicology 285:8–17PubMed

88.

Zhang J-S, Li D-M, Ma Y, He N, Gu Q, Wang F-S, Jiang S-Q, Chen B-Q, Liu J-R (2013) γ-Tocotrienol induces paraptosis-like cell death in human colon carcinoma SW620 cells. PLoS One 8(2):e57779PubMedPubMedCentral

89.

Fontana F, Moretti RM, Raimondi M, MarzagallI M, Beretta G, Procacci P, Sartori P, Montagnani Marelli M, Limonta P (2019) δ-Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells. Cell Prolif. https://doi.org/10.1111/cpr.12576 CrossRefPubMedPubMedCentral

90.

Wang H, Luo J, Tian W, Yan W, Ge S, Zhang Y, Sun W (2019) γ-Tocotrienol inhibits oxidative phosphorylation and triggers apoptosis by inhibiting mitochondrial complex I subunit NDUFB8 and complex II subunit SDHB. Toxicology 417:42–53PubMed

91.

Liu H, Wang Q, Li Y, Sun W, Liu J, Yang Y, Xu W, Sun X, Chen B (2010) Inhibitory effects of gamma-tocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 21(3):206–213. https://doi.org/10.1016/j.jnutbio.2008.11.004 CrossRefPubMed

92.

Nakagawa K, Eitsuka T, Inokuchi H, Miyazawa T (2004) DNA chip analysis of comprehensive food function: inhibition of angiogenesis and telomerase activity with unsaturated vitamin E, tocotrienol. BioFactors 21(1–4):5–10. https://doi.org/10.1002/biof.552210102 CrossRefPubMed

93.

Shibata A, Nakagawa K, Tsuduki T, Oikawa S, Miyazawa T (2009) δ-Tocotrienol suppresses VEGF induced angiogenesis whereas α-tocopherol does not. J Agric Food Chem 57(18):8696–8704PubMed

94.

Weng-Yew W, Selvaduray KR, Ming CH, Nesaretnam K (2009) Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis. Nutr Cancer 61(3):367–373. https://doi.org/10.1080/01635580802582736 CrossRefPubMed

95.

Selvaduray KR, Nesaretnam K, Radhakrishnan AK, Kutty MK (2012) Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells. Genes Nutr 7(1):53–61. https://doi.org/10.1007/s12263-011-0223-0 CrossRefPubMed

96.

Selvaduray KR, Nesaretnam K, Radhakrishnan AK, Kutty MK (2010) Palm tocotrienols inhibit proliferation of murine mammary cancer cells and induce expression of interleukin-24 mRNA. J Interferon Cytokine Res 30(12):909–916PubMed

97.

Luk SU, Chiu Y, Lee DTW, Wong Y, Ching YP, Yap WN, Yap YL, Ma S, Lee TKW, Vasireddy RS, Nelson C, Ling M-T (2011) Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population. Int J Cancer 128(9):2182–2191. https://doi.org/10.1002/ijc.25546 CrossRefPubMed

98.

Lee OK, Ma Z, Yeh C-R, Luo T, Lin T-H, Lai KP et al (2013) New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells. J Mol Cell Biol 5:14–26PubMed

99.

Kaneko S, Sato C, Shiozawa N, Sato A, Sato H, Virgona N, Yano T (2018) Suppressive effect of delta-tocotrienol on hypoxia adaptation of prostate cancer stem-like cells. Anticancer Res 38(3):1391–1399PubMed

100.

Gopalan A, Yu W, Sanders BG, Kline K (2013) Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett 328:285–296PubMed

101.

Xiong A, Yu W, Liu Y, Sanders BG, Kline K (2016) Elimination of ALDHþ breast tumor initiating cells by docosahexanoic acid and/or gamma tocotrienol through SHP-1 inhibition of STAT3 signaling. Mol Carcinog 55:420–430PubMed

102.

Gu W, Prasadam I, Yu M, Zhang F, Ling P, Xiao Y, Yu C (2015) Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway. BMC Cancer 15:609PubMedPubMedCentral

103.

Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP (2017) δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis. Oncotarget 8(19):31554–31567PubMedPubMedCentral

104.

Komiyama K, Iizuka K, Yamaoka M, Watanabe H, Tsuchiya N, Umezawa I (1989) Studies on the biological activity of tocotrienols. Chem Pharm Bull 37(5):1369–1371PubMed

105.

Hiura Y, Tachibana H, Arakawa R, Aoyama N, Okabe M, Sakai M, Yamada K (2009) Research article: specific accumulation of γ- and δ-tocotrienols in tumor and their antitumor effect in vivo. J Nutr Biochem 20:607–613. https://doi.org/10.1016/j.jnutbio.2008.06.004 CrossRefPubMed

106.

Siveen KS, Shanmugam MK, Li F, Yap WN, Kumar AP, Sethi G, Ahn KS, Ong TH, Hui KM, Fong CW, Tergaonkar V (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):1897–1911. https://doi.org/10.18632/oncotarget.1876 CrossRefPubMedPubMedCentral

107.

Manu KA, Shanmugam MK, Ramachandran L, Li F, Kumar AP, Sethi G, Tan P, Fong CW (2012) First evidence that γ-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-κB pathway. Clin Cancer Res 18(8):2220–2229. https://doi.org/10.1158/1078-0432.CCR-11-2470 CrossRefPubMed

108.

Jiang Q, Rao X, Kim CY, Freiser H, Zhang Q, Jiang Z, Li G (2012) Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide. Int J Cancer 130(3):685–693. https://doi.org/10.1002/ijc.26054 CrossRefPubMed

109.

Shen M, Hang Chan T, Ping Dou Q (2012) Targeting tumor ubiquitin-proteasome pathway with polyphenols for chemosensitization. Anticancer Agents Med Chem 12(8):891–901PubMedPubMedCentral

110.

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):814–824. https://doi.org/10.1038/bjc.2016.257 CrossRefPubMedPubMedCentral

111.

Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey S, Koca C, Yadav VR, Tong Z, Gelovani JG, Guha S, Krishnan S, Aggarwal BB (2010) {Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment. Can Res 70(21):8695–8705. https://doi.org/10.1158/0008-5472.CAN-10-2318 CrossRef

112.

Bachawal SV, Wali VB, Sylvester PW (2010) Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells. BMC Cancer 10:84. https://doi.org/10.1186/1471-2407-10-84 CrossRefPubMedPubMedCentral

113.

Kannappan R, Yadav VR, Aggarwal BB (2016) Correction: γ-Tocotrienol but not γ-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents (Journal of Biological Chemistry (2010) 285 (33520-33528)). J Biol Chem 291(32):16922. https://doi.org/10.1074/jbc.A110.158378 CrossRefPubMedPubMedCentral

114.

Kani K, Momota Y, Harada M, Yamamura Y, Aota K, Yamanoi T, Takano H, Motegi K, Azuma M (2013) γ-Tocotrienol enhances the chemosensitivity of human oral cancer cells to docetaxel through the downregulation of the expression of NF-κB-regulated anti-apoptotic gene products. Int J Oncol 42(1):75–82. https://doi.org/10.3892/ijo.2012.1692 CrossRefPubMed

115.

Gu W, Prasadam I, Yu M, Zhang F, Ling P, Xiao Y, Yu C (2015) Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway. BMC Cancer 15(1):1

116.

Aykin-Burns N, Pathak R, Boerma M, Kim T, Hauer-Jensen M (2019) Utilization of vitamin E analogs to protect normal tissues while enhancing antitumor effects. Semin Radiat Oncol 29(1):55–61PubMedPubMedCentral

117.

Murtaugh MA, Ma K, Benson J, Curtin K, Caan B, Slattery ML (2004) Antioxidants, carotenoids, and risk of rectal cancer. Am J Epidemiol 159(1):32–41PubMed

118.

ATBC Cancer Prevention Study Group (1994) The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann Epidemiol 4(1):1–10

119.

Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Mäenpää H, Teerenhovi L, Koss L, Virolainen M, Edwards BK (1998) Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 90(6):440–446PubMed

120.

Virtamo J, Taylor PR, Kontto J, Männistö S, Utriainen M, Weinstein SJ, Huttunen J, Albanes D (2014) Effects of α-tocopherol and β-carotene supplementation on cancer incidence and mortality: 18-year postintervention follow-up of the alpha-tocopherol, beta-carotene Cancer Prevention Study. Int J Cancer 135(1):178–185. https://doi.org/10.1002/ijc.28641 CrossRefPubMed

121.

Lee I, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the women’s health study: a randomized controlled trial. JAMA 294(1):56PubMed

122.

Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers. JAMA 301(1):39–51PubMed

123.

Springett GM, Husain K, Hutchinson TZ, Malafa MP, Neuger A, Lush RM, Centeno B, Chen D, Sebti S (2015) A phase I safety, pharmacokinetic, and pharmacodynamic presurgical trial of vitamin E δ-tocotrienol in patients with pancreatic ductal neoplasia. EBioMedicine 2(12):1987–1995. https://doi.org/10.1016/j.ebiom.2015.11.025 CrossRefPubMedPubMedCentral

124.

Mahipal A, Klapman J, Vignesh S, Yang CS, Neuger A, Chen D, Malafa MP (2016) Pharmacokinetics and safety of vitamin E d-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites. Cancer Chemother Pharmacol 78(1):157–165. https://doi.org/10.1007/s00280-016-3048-0 CrossRefPubMedPubMedCentral

125.

Shen C, Yang S, Tomison MD, Mo H, Wang S, Felton CK, Soelaiman IN (2016) Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial. BMJ Open 6(12):6. https://doi.org/10.1136/bmjopen-2016-012572 CrossRef

126.

Nesaretnam K, Selvaduray KR, Abdul Razak G, Veerasenan SD, Gomez PA (2010) Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial. Breast Cancer Res 12:R81. https://doi.org/10.1186/bcr2726 CrossRefPubMedPubMedCentral

Title: Vitamin E and cancer: an update on the emerging role of γ and δ tocotrienols
Authors: Constantina Constantinou
Christiana Charalambous
Dimitrios Kanakis
Publication date: 01-04-2020
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nutrition / Issue 3/2020
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-019-01962-1

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2020

Diets containing the highest levels of dairy products are associated with greater eutrophication potential but higher nutrient intakes and lower financial cost in the United Kingdom

Iodine-fortified toddler milk improves dietary iodine intakes and iodine status in toddlers: a randomised controlled trial

Adherence to a priori dietary indexes and baseline prevalence of cardiovascular risk factors in the PREDIMED-Plus randomised trial

Associations between long-term adherence to healthy diet and recurrent depressive symptoms in Whitehall II Study

Micronutrient status and leukocyte telomere length in school-age Colombian children

Consumption of fried foods and risk of atrial fibrillation in the Physicians' Health Study

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage