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Recent Patents on Anti-Cancer Drug Discovery


ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Review Article

Tocotrienols and Cancer: From the State of the Art to Promising Novel Patents

Author(s): Fabrizio Fontana, Michela Raimondi, Monica Marzagalli, Roberta M. Moretti, Marina Montagnani Marelli and Patrizia Limonta*

Volume 14, Issue 1, 2019

Page: [5 - 18] Pages: 14

DOI: 10.2174/1574892814666190116111827


Background: Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.

Objective: The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.

Methods: Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.

Results: TTs have demonstrated significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.

Conclusion: The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities for therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

Keywords: Cancer prevention, cancer therapy, natural compounds, tocotrienols, tocotrienol formulations, tocotrienol synthetic derivatives.

Kalra EK. Nutraceutical: Definition and introduction. AAPS PharmSci 2003; 5: E25.
Ahsan H, Ahad A, Iqbal J, Siddiqui WA. Pharmacological potential of tocotrienols: A review. Nutr Metab (Lond) 2014; 11: 52-9.
Montagnani MM, Marzagalli M, Fontana F, Raimondi M, Moretti RM, Limonta P. Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets. J Cell Physiol 2018.
De Silva L, Chuah LH, Meganathan P, Fu JY. Tocotrienol and cancer metastasis. BioFactors 2016; 42: 149-62.
Kannappan R, Gupta SC, Kim JH, Aggarwal BB. Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes Nutr 2012; 7: 43-52.
Evans HM, Bishop KS. Existence of a hitherto unknown dietary factor essential for reproduction. J Am Med Assoc 1923; 81: 889-92.
Evans HM. The isolation from wheat germ oil of an alcohol, α-tocopherol, having the properties of vitamin E. J Biol Chem 1936; 113: 319-32.
Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Asai A, Miyazawa T. α-Tocopherol attenuates the cytotoxic effect of δ-tocotrienol in human colorectal adenocarcinoma cells. Biochem Biophys Res Commun 2010; 397: 214-9.
Uchida T, Abe C, Nomura S, Ichikawa T, Ikeda S. Tissue distribution of α- and γ-tocotrienol and γ-tocopherol in rats and interference with their accumulation by α-tocopherol. Lipids 2012; 47: 129-39.
Khan MR, Siddiqui S, Parveen K, Javed S, Diwakar S, Siddiqui WA. Nephroprotective action of tocotrienol-rich fraction (TRF) from palm oil against potassium dichromate (K2Cr2O7)-induced acute renal injury in rats. Chem Biol Interact 2010; 186: 228-38.
Khanna S, Patel V, Rink C, Roy S, Sen CK. Delivery of orally supplemented α-tocotrienol to vital organs of rats and tocopherol-transport protein deficient mice. Free Radic Biol Med 2005; 39: 1310-9.
Qureshi AA, Khan DA, Mushtaq S, Ye SQ, Xiong M, Qureshi N. δ-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling pathways in chronic hepatitis C patients. Lipids Health Dis 2018; 17: 167.
Bartosińska E, Jacyna J, Borsuk DA, Kaliszan M, Kruszewski WJ, Jankowski Z, et al. HPLC-APCI-MS/MS method development and validation for determination of tocotrienols in human breast adipose tissue. Talanta 2018; 176: 108-15.
Springett GM, Husain K, Neuger A, Centeno B, Chen D-T, Hutchinson TZ, et al. A Phase I safety, pharmacokinetic, and pharmacodynamic presurgical trial of vitamin e δ-tocotrienol in patients with pancreatic ductal neoplasia. BioMedicine 2015; 2: 1987-95.
Mei HN, Yuen MC, Ah NM, Cheng HC, Hashim MA. Separation of vitamin E (tocopherol, tocotrienol, and tocomonoenol) in palm oil. Lipids 2004; 39: 1031-5.
Raddatz-Mota D, Pérez-Flores LJ, Carrari F, Mendoza-Espinoza JA, de León-Sánchez FD, Pinzón-López LL, et al. Achiote (Bixa orellana L.): A natural source of pigment and vitamin E. J Food Sci Technol 2017; 54: 1729-41.
Goufo P, Trindade H. Rice antioxidants: Phenolic acids, flavonoids, anthocyanins, proanthocyanidins, tocopherols, tocotrienols, γ-oryzanol, and phytic acid. Food Sci Nutr 2014; 2: 75-104.
Min B, McClung AM, Chen M-H. Phytochemicals and antioxidant capacities in rice brans of different color. J Food Sci 2011; 76: C117-26.
Shahidi F, De Camargo AC. Tocopherols and tocotrienols in common and emerging dietary sources: Occurrence, applications, and health benefits. Int J Mol Sci 2016; 10: 1745.
Ahsan H, Ahad A, Siddiqui WA. A review of characterization of tocotrienols from plant oils and foods. J Chem Biol 2015; 8: 45-59.
Prasad K. Tocotrienols and cardiovascular health. Curr Pharm Des 2011; 17: 2147-54.
Chin KY, Tay SS. A Review on the relationship between tocotrienol and Alzheimer disease. Nutrients 2018; 10: 881.
Abdul-Majeed S, Mohamed N, Soelaiman I-N. A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis. Curr Drug Targets 2013; 14: 1579-90.
Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, et al. Tocotrienols for bone health: A translational approach. Ann N Y Acad Sci 2017; 1401: 150-65.
Hsieh TC, Elangovan S, Wu JM. 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 2010; 30: 2869-74.
Samant GV, Wali VB, Sylvester PW. Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif 2010; 43: 77-83.
Parajuli P, Tiwari RV, Sylvester PW. Anti-proliferative effects of γ-tocotrienol are associated with suppression of c-Myc expression in mammary tumour cells. Cell Prolif 2015; 48: 421-35.
Takahashi K, Loo G. Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells. Biochem Pharmacol 2004; 67: 315-24.
Loganathan R, Selvaduray KR, Nesaretnam K, Radhakrishnan AK. Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity. Cell Prolif 2013; 46: 203-13.
Shah S, Sylvester PW. Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary epithelial cells. Exp Biol Med 2004; 229: 745-55.
Khallouki F, de Medina P, Caze-Subra S, Bystricky K, Balaguer P, Poirot M, et al. Molecular and biochemical analysis of the estrogenic and proliferative properties of vitamin E compounds. Front Oncol 2016; 5: 287.
Viola V, Ciffolilli S, Legnaioli S, Piroddi M, Betti M, Mazzini F, et al. Mitochondrial-dependent anticancer activity of δ-tocotrienol and its synthetic derivatives in HER-2/neu overexpressing breast adenocarcinoma cells. BioFactors 2013; 39: 485-93.
Asif HM, Sultana S, Ahmed S, Akhtar N, Tariq M. HER-2 positive breast cancer - A mini-review. Asian Pac J Cancer Prev 2016; 17: 1609-15.
Alawin OA, Ahmed RA, Ibrahim BA, Briski KP, Sylvester PW. Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells. J Nutr Biochem 2016; 27: 266-77.
Comitato R, Leoni G, Canali R, Ambra R, Nesaretnam K, Virgili F. Tocotrienols activity in MCF-7 breast cancer cells: Involvement of ERβ signal transduction. Mol Nutr Food Res 2010; 54: 669-78.
Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J 2016; 283: 2640-52.
Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. J Pathol 2010; 221: 3-12.
Wang M, Law ME, Castellano RK, Law BK. The unfolded protein response as a target for anticancer therapeutics. Crit Rev Oncol Hematol 2018; 127: 66-79.
Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer 2017; 17: 528-42.
Kim C, Kim B. Anti-cancer natural products and their bioactive compounds inducing ER stress-mediated apoptosis: A review. Nutrients 2018; 10: 1021.
Lin SR, Fu YS, Tsai MJ, Cheng H, Weng CF. Natural compounds from herbs that can potentially execute as autophagy inducers for cancer therapy. Int J Mol Sci 2017; 18: 1412-9.
Wali VB, Bachawal SV, Sylvester PW. Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis 2009; 14: 1366-77.
Park SK, Sanders BG, Kline K. Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 2010; 124: 361-75.
Patacsil D, Tran AT, Cho YS, Suy S, Saenz F, Malyukova I, et al. Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells. J Nutr Biochem 2011; 23: 93-100.
Tiwari RV, Parajuli P, Sylvester PW. γ-Tocotrienol-induced autophagy in malignant mammary cancer cells. Exp Biol Med 2014; 239: 33-44.
Tiwari RV, Parajuli P, Sylvester PW. γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death. Biochem Cell Biol 2015; 93: 306-20.
Sylvester PW. Targeting met mediated epithelial-mesenchymal transition in the treatment of breast cancer. Clin Transl Med 2014; 3: 30.
Selvaduray KR, Radhakrishnan AK, Kutty MK, Nesaretnam K. Palm tocotrienols inhibit proliferation of murine mammary cancer cells and induce expression of interleukin-24 mRNA. J Interf Cytokine Res 2010; 30: 909-16.
Selvaduray KR, Radhakrishnan AK, Kutty MK, Nesaretnam K. Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells. Genes Nutr 2012; 7: 53-61.
Algayadh IG, Dronamraju V, Sylvester PW. Role of Rac1/WAVE2 signaling in mediating the inhibitory effects of gamma-tocotrienol on mammary cancer cell migration and invasion. Biol Pharm Bull 2016; 39: 1974-82.
Nassar D, Blanpain C. Cancer stem cells: Basic concepts and therapeutic implications. Annu Rev Pathol Mech Dis 2016; 11: 47-76.
Taylor WF, Jabbarzadeh E. The use of natural products to target cancer stem cells. Am J Cancer Res 2017; 7: 1588-605.
Gopalan A, Yu W, Sanders BG, Kline K. Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett 2013; 328: 285-96.
Xiong A, Yu W, Liu Y, Sanders BG, Kline K. Elimination of ALDH+ breast tumor initiating cells by docosahexanoic acid and/or gamma tocotrienol through SHP-1 inhibition of Stat3 signaling. Mol Carcinog 2016; 55: 420-30.
Bachawal SV, Wali VB, Sylvester PW. Combined γ-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res 2010; 30: 429-37.
Wali VB, Sylvester PW. Synergistic antiproliferative effects of γ-tocotrienol and statin treatment on mammary tumor cells. Lipids 2007; 42: 1113-23.
W. Sylvester P. Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment. J Bioanal Biomed 2011; 3: 1-7.
Ding Y, Peng Y, Deng L, Fan J, Huang B. Gamma-tocotrienol reverses multidrug resistance of breast cancer cells with a mechanism distinct from that of atorvastatin. J Steroid Biochem Mol Biol 2017; 167: 67-77.
Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem 2002; 277: 25290-6.
Akl MR, Ayoub NM, Sylvester PW. Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and sesamin treatment. Planta Med 2012; 78: 1731-9.
Akl MR, Ayoub NM, Abuasal BS, Kaddoumi A, Sylvester PW. Sesamin synergistically potentiates the anticancer effects of γ-tocotrienol in mammary cancer cell lines. Fitoterapia 2013; 84: 347-59.
Hsieh TC, Wu JM. 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 2008; 33: 851-9.
Tiwari RV, Parajuli P, Sylvester PW. Synergistic anticancer effects of combined γ-tocotrienol and oridonin treatment is associated with the induction of autophagy. Mol Cell Biochem 2015; 408: 123-37.
Behery FA, Akl MR, Ananthula S, Parajuli P, Sylvester PW, El Sayed KA. Optimization of tocotrienols as antiproliferative and antimigratory leads. Eur J Med Chem 2013; 59: 329-41.
Ananthula S, Parajuli P, Behery FA, Alayoubi AY, El Sayed KA, Nazzal S, et al. Oxazine derivatives of γ- and δ-tocotrienol display enhanced anticancer activity in vivo. Anticancer Res 2014; 34: 2715-26.
Ananthula S, Parajuli P, Behery FA, Alayoubi AY, Nazzal S, El Sayed K, et al. δ-Tocotrienol oxazine derivative antagonizes mammary tumor cell compensatory response to COCl2-induced hypoxia. Biomed Res Int 2014; 2014: 285752.
Nesaretnam K, Selvaduray KR, Abdul Razak G, Veerasenan SD, Gomez PA. Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial. Breast Cancer Res 2010; 12: R81.
Wu S-J, Ng L-T. Tocotrienols inhibited growth and induced apoptosis in human HeLa cells through the cell cycle signaling pathway. Integr Cancer Ther 2010; 9: 66-72.
Comitato R, Guantario B, Leoni G, Nesaretnam K, Ronci MB, Canali R, et al. Tocotrienols induce endoplasmic reticulum stress and apoptosis in cervical cancer cells. Genes Nutr 2016; 11: 32.
Gu W, Prasadam I, Yu M, Zhang F, Ling P, Xiao Y, et al. Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway. BMC Cancer 2015; 15: 609.
Agarwal MK, Agarwal ML, Athar M, Gupta S. Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle 2004; 3: 205-11.
Jang Y, Rao X, Jiang Q. 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 2017; 46: 49-56.
Lee D, Kim IY, Saha S, Choi KS. Paraptosis in the anti-cancer arsenal of natural products. Pharmacol Ther 2016; 162: 120-33.
Zhang JS, Li DM, Ma Y, He N, Gu Q, Wang F-S, et al. γ-Tocotrienol induces paraptosis-like cell death in human colon carcinoma SW620 cells. PLoS One 2013; 8: e57779.
Zhang JS, Li DM, He N, Liu YH, Wang CH, Jiang S-Q, et al. 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 2011; 285: 8-17.
Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. 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 2016; 115: 814-24.
Yang Z, Xiao H, Jin H, Koo PT, Tsang DJ, Yang CS. Synergistic actions of atorvastatin with gamma-tocotrienol and celecoxib against human colon cancer HT29 and HCT116 cells. Int J Cancer 2010; 126: 852-63.
Md Yusof K, Makpol S, Jamal R, Harun R, Mokhtar N, Wan Ngah W. γ-Tocotrienol and 6-gingerol in combination synergistically induce cytotoxicity and apoptosis in HT-29 and SW837 human colorectal cancer cells. Molecules 2015; 20: 10280-97.
Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Tomita S, Shirakawa H, et al. Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing Hypoxia-Inducible Factor-1α. J Nutr 2008; 138: 2136-42.
Shibata A, Nakagawa K, Sookwong P, Tsuzuki T, Oikawa S, Miyazawa T. Tumor anti-angiogenic effect and mechanism of action of δ-tocotrienol. Biochem Pharmacol 2008; 76: 330-9.
Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S, Mlyazawa T. δ-tocotrienol suppresses VEGF induced angiogenesis whereas α-tocopherol does not. J Agric Food Chem 2009; 57: 8696-704.
Eitsuka T, Tatewaki N, Nishida H, Nakagawa K, Miyazawa T. A combination of δ-tocotrienol and ferulic acid synergistically inhibits telomerase activity in DLD-1 human colorectal adenocarcinoma cells. J Nutr Sci Vitaminol 2016; 62: 281-7.
Sun W, Wang Q, Chen B, Liu J, Liu H, Xu W. 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 2008; 99: 1247-54.
Sun W, Xu W, Liu H, Liu J, Wang Q, Zhou J, et al. γ-Tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 2009; 20: 276-84.
Liu H-K, Wang Q, Li Y, Sun W-G, Liu J-R, Yang Y-M, et al. Inhibitory effects of γ-tocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 2010; 21: 206-13.
Bi S, Liu JR, Li Y, Wang Q, Liu HK, Yan YG, et al. γ-Tocotrienol modulates the paracrine secretion of VEGF induced by cobalt(II) chloride via ERK signaling pathway in gastric adenocarcinoma SGC-7901 cell line. Toxicology 2010; 274: 27-33.
Li Y, Sun W-G, Liu H-K, Qi G-Y, Wang Q, Sun X-R, et al. γ-Tocotrienol inhibits angiogenesis of human umbilical vein endothelial cell induced by cancer cell. J Nutr Biochem 2011; 22: 1127-36.
Manu KA, Shanmugam MK, Ramachandran L, Li F, Fong CW, Kumar AP, et al. 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 2012; 18: 2220-9.
Peng Y, Croce CM. The role of microRNAS in human cancer. Signal Transduct Target Ther 2016; 1: 15004.
Ji X, Wang Z, Geamanu A, Goja A, Sarkar FH, Gupta SV. Delta-tocotrienol suppresses Notch-1 pathway by upregulating miR-34a in nonsmall cell lung cancer cells. Int J Cancer 2012; 131: 2668-77.
Ji X, Wang Z, Sarkar FH, Gupta SV. Delta-tocotrienol augments cisplatin-induced suppression of non-small cell lung cancer cells via inhibition of the Notch-1 pathway. Anticancer Res 2012; 32: 2647-55.
McAnally J a, Gupta J, Sodhani S, Bravo L, Mo H. Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. Exp Biol Med (Maywood) 2007; 232: 523-31.
Hodul PJ, Dong Y, Husain K, Pimiento JM, Chen J, Zhang A, et al. Vitamin E δ-Tocotrienol induces p27Kip1-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism. PLoS One 2013; 8: e52526.
Hussein D, Mo H. d-δ-Tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 Pancreatic Carcinoma Cells. Pancreas 2009; 38: e124-36.
Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, Stone W, Campbell S, et al. Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 2011; 51: 1164-74.
Wang C, Husain K, Zhang A, Centeno BA, Chen D-T, Tong Z, et al. EGR-1/Bax pathway plays a role in vitamin E δ-tocotrienol-induced apoptosis in pancreatic cancer cells. J Nutr Biochem 2015; 26: 797-807.
Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey S, et al. γ-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment. Cancer Res 2010; 70: 8695-705.
Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP. δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis. Oncotarget 2017; 8: 31554-67.
Abu-Fayyad A, Nazzal S. Synthesis, characterization, and in vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E. Int J Pharm 2017; 519: 145-56.
Abu-Fayyad A, Nazzal S. Gemcitabine-vitamin E conjugates: Synthesis, characterization, entrapment into nanoemulsions, and in-vitro deamination and antitumor activity. Int J Pharm 2017; 528: 463-70.
Abu-Fayyad A, Kamal MM, Carroll JL, Dragoi A-M, Cody R, Cardelli J, et al. Development and in vitro characterization of nanoemulsions loaded with paclitaxel/γ-tocotrienol lipid conjugates. Int J Pharm 2018; 536: 146-57.
Yap WN, Chang PN, Han HY, Lee DTW, Ling MT, Wong YC, et al. Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer 2008; 99: 1832-41.
Barve A, Khor TO, Reuhl K, Reddy B, Newmark H, Kong A-N. Mixed tocotrienols inhibit prostate carcinogenesis in TRAMP mice. Nutr Cancer 2010; 62: 789-94.
Campbell SE, Rudder B, Phillips RB, Whaley SG, Stimmel JB, Leesnitzer LM, et al. γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer. Free Radic Biol Med 2011; 50: 1344-54.
Sugahara R, Sato A, Uchida A, Shiozawa S, Sato C, Virgona N, et al. Annatto tocotrienol induces a cytotoxic effect on human prostate cancer PC3 cells via the simultaneous inhibition of Src and Stat3. J Nutr Sci Vitaminol (Tokyo) 2015; 61: 497-501.
Huang Y, Wu R, Su ZY, Guo Y, Zheng X, Yang CS, et al. 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 2017; 40: 155-63.
Luk SU, Yap WN, Chiu YT, Lee DTW, Ma S, Lee TKW, et al. Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population. Int J Cancer 2011; 128: 2182-91.
Lee SO, Ma Z, Yeh C-R, Luo J, Lin T-H, Lai K-P, et al. New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells. J Mol Cell Biol 2013; 5: 14-26.
Kaneko S, Sato C, Shiozawa N, et al. Suppressive Effect of delta-tocotrienol on hypoxia adaptation of prostate cancer stem-like cells. Anticancer Res 2018; 38(3): 1391-9.
Mo H, Elson CE. Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Exp Biol Med (Maywood) 2004; 229: 567-85.
Yeganehjoo H, DeBose-Boyd R, McFarlin BK, Mo H. Synergistic impact of d-δ-tocotrienol and geranylgeraniol on the growth and HMG CoA reductase of human DU145 Prostate carcinoma cells. Nutr Cancer 2017; 69: 682-91.
Montagnani Marelli M, Marzagalli M, Moretti RM, Beretta G, Casati L, Comitato R, et al. Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells. Sci Rep 2016; 6: 30502.
Marzagalli M, Moretti RM, Messi E, Montagnani Marelli M, Fontana F, Anastasia A, et al. Targeting melanoma stem cells with the Vitamin E derivative δ-tocotrienol. Sci Rep 2018; 8: 587.
Chang PN, Yap WN, Lee DTW, Ling MT, Wong YC, Yap YL. Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. Nutr Cancer 2009; 61: 357-66.
Kawajiri K, Fujii-Kuriyama Y. The aryl hydrocarbon receptor: A multifunctional chemical sensor for host defense and homeostatic maintenance. Exp Anim 2017; 66: 75-89.
Yamashita S, Baba K, Makio A, Kumazoe M, Huang Y, Lin I-C, et al. γ-Tocotrienol upregulates aryl hydrocarbon receptor expression and enhances the anticancer effect of baicalein. Biochem Biophys Res Commun 2016; 473: 801-7.
Pham J, Nayel A, Hoang C, Elbayoumi T. Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas. Drug Deliv 2016; 23: 1514-24.
Ledet G, Biswas S, Kumar V, Graves R, Mitchner D, Parker T, et al. Development of orally administered γ-tocotrienol (GT3) nanoemulsion for radioprotection. Int J Mol Sci 2016; 18: 28.
Karim R, Somani S, Al Robaian M, Mullin M, Amor R, McConnell G, et al. Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol. J Control Release 2017; 246: 79-87.
Ye C, Zhao W, Li M, Zhuang J, Yan X, Lu Q, et al. δ-Tocotrienol induces human bladder cancer cell growth arrest, apoptosis and chemosensitization through inhibition of STAT3 pathway. PLoS One 2015; 10: e0122712.
Tan JK, Then SM, Mazlan M, Raja Abdul Rahman RNZ, Jamal R, Wan Ngah WZ. Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells. J Nutr Biochem 2016; 31: 28-37.
Inoue A, Takitani K, Koh M, Kawakami C, Kuno T, Tamai H. Induction of apoptosis by α-Tocotrienol in human cancer cell lines and leukemic blasts from patients: Dependency on bid, cytochrome c, and caspase pathway. Nutr Cancer 2011; 63: 763-70.
Wilankar C, Khan NM, Checker R, Sharma D, Patwardhan R, Gota V, et al. γ-Tocotrienol induces apoptosis in human T cell lymphoma through activation of both intrinsic and extrinsic pathways. Curr Pharm Des 2011; 17: 2176-89.
Burdeos GC, Ito J, Eitsuka T, Nakagawa K, Kimura F, Miyazawa T. δ and γ tocotrienols suppress human hepatocellular carcinoma cell proliferation: Via regulation of Ras-Raf-MEK-ERK pathway-associated upstream signaling. Food Funct 2016; 7: 4170-4.
Siveen KS, Ahn KS, Ong TH, et al. Gamma-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget 2014; 5(7): 1897-911.
Fu JY, Htar TT, De Silva L, Tan DMY, Chuah LH. Chromatographic Separation of vitamin E enantiomers. Molecules 2017; 22: 233.
Beretta G, Gelmini F, Fontana F, Moretti RM, Montagnani Marelli M, Limonta P. Semi-preparative HPLC purification of δ-tocotrienol (δ-T3) from Elaeis guineensis Jacq. and Bixa orellana L. and evaluation of its in vitro anticancer activity in human A375 melanoma cells. Nat Prod Res 2018; 32: 1130-5.
Top AG, Leong LW, Ong ASH, Kawada T, Watanabe H, Tsuchiya N. Production of high concentration tocopherols and tocotrienols from palm-oil by-products. US5190618 (1993)
Furuse T, Iwama T, Kishima S, Sakaguchi T, Ueishi S. Method for producing fatty acid concentrate of tocopherol and tocotrienol. JP2002003488 (2002)
Ichitani T, Tanaka Y. Tocopherol concentrate and tocotrienol concentrate, and method for producing the same. JP2003171376 (2003)
Kishima S, Nakatate M. Method for producing tocopherol and tocotrienol. JP2004305155 (2004)
Jacobs L. Process for the production of tocotrienols. US6838104 (2005)
Dai Z, Li X, Zhao J, Wang S, Xu X, Shao B. Preparation method of high-purity tocopherol and tocotrienol concentrate mixture. CN106632209 (2017)
Yin J, Zhang Y, Huang Y, Huang H. High-efficiency tocotrienol purifying method. CN107417658 (2017)
Tan B, Saleh MH. Integrated process for recovery of carotenoids and tocotrienols from oil. US5157132 (1992)
Tou GP. Recovery of minor components from vegetable oils and fats. GB2387390 (2003)
Shaohua L, Nana M, Caiyun M, Shije Z, Jingfang Z. Natural carotenoid and tocotrienol-enriched red palm oil. CN102187914 (2011)
Goh RSH, Kam RTS. Recovery of carotenoids, tocopherols, tocotrienols and sterols from esterified palm oil. GB2218989 (1991)
Choo YM, Ma AN, Basiron DY. A method of chromatographic isolation for vitamin E isomers. CA2334068 (2010)
Zhao Y, Sun M, Huang S, Sun R. Method for enriching mixture of natural totaxin and natural tocotrienol and extraction system. CN106215448 (2018)
Lee YS, Park SR, Kim YH, Kang CS. A method of massproduction tocotrienol in rice bran and bran-based functional foodstuff containing tocotrienol with high content. KR100884570 (2009)
Maeda Y, Hoang TT, Takahashi H, Matsubara T. Method for producing bioactive substance from rice bran. JP6335026 (2018)
Tan B, Foley J. Tocotrienols and geranylgeraniol from Bixa orellana byproducts. US6350453 (2002)
Honma R, Abe H, Ishikura Y. Method for producing A tocotrienol composition. JP5272073 (2013)
Howard L. Process of producing purified gamma- and deltatocotrienols from tocol-rich oils or distillates. US9512098 (2016)
Babura SR, Abdullah SNA, Khaza AH. Advances in genetic improvement for tocotrienol production: A review. J Nutr Sci Vitaminol 2017; 63: 215-21.
Park HM, Kim YH, Lee YY, Lee SB, Lee JS. Composition for preventing or treating prostate cancer comprising rice transformed with tocotrienol biosynthesis gene. KR101629370 (2016)
Kim YH, Lee YY, Park HM, et al. Germinated transformants synthesizing tocotrienol with high anti-oxidant activity. KR101303741 (2015)
Lee YS, Tariq HMMH, Kim KH, Kim YH. Transgenic perilla having increased tocotrienol content. KR100970379 (2010)
Dobashi K, Mori H, Murai H, Okada T, Yoshimi N. Colon cancer-preventing agent. JP2002316940 (2002))
Ling MT, Yap WN, Wong YC, Yap YLD. Use of tocotrienol composition for the prevention of cancer. US20110195910 ( (2011)
Malafa MP, Sebti SM. Delta-tocotrienol treatment and prevention of pancreatic cancer. US8288369 (2012)
Lane RH, Qureshi AA, Salser WA. Tocotrienols and tocotrienol-like compounds and methods for their use. US5591772 (1997)
Ikushima H, Miyazawa T. Tocotrienols as inhibitors for neovascularization. EP1230923 (2006)
Yamada K, Yoshitake S, Asano T. Immune function improving agent. JP4271742 (2009)
Nesadurai K, Selvaduray KR, Hafid SRA, Razak GA, Huat OT. Transdermal fluid. US20080194677 (2008)
Tien YD. Chemoprotective/chemoactive nanodroplets and methods of use thereof. WO2018005412 (2018)
Tong G. Transmucosal delivery of tocotrienol. WO2014075135 (2014)
Erfinder WSG. Use of an active ingredient consisting of e.g. tocotrienols in the substantial absence of tocopherols, for the prevention or treatment of e.g. normal or pathological inflammatory diseases, pain, diseases of nervous system, and cancer. DE102012020542 (2014)
Guthrie N, Kurowska EM, Carroll KK. Compositions and methods of treatment of neoplastic diseases and hypercholesterolemia with citrus limonoids and flavonoids and tocotrienols. US6251400 (2001)
Nesaretnam K, Selvaduray KR. Synergistic effect of tocotrienols and curcumin. US8906960 ( (2014)
Elson CE. Method of suppressing tumor growth with combinations of isoprenoids and statins. EP0986383 (2000)
Mo H, Elson CE, Peffley DM, Hentosh PM. Composition and method for treating cancer. US7074825 (2006)
Bellafiore L, Radosevich JA, Glicken E. Tocotrienol compositions. US20110293753 (2011)
Sylvester PW. Anticancer combination treatments. US20130143866 (2013)
Naidu AS, Naidu AGS, Naidu AGT. Metallo-protein and tocotrienol (MP-T3) compositions and uses thereof. US8309080 (2012)
Schneider FH, Lane RH, Avila T. Novel antioxidant formulations and methods for using them. WO2000057876 (2000)
Hasler-Nguyen N, Zijlstra J, Troup JP. Synergistic antioxidant combination of delta tocols and polyphenols. US7452549 (2008)
Babish J, Howell T. Compositions containing carotenoids and tocotrienols and having synergistic antioxidant effect. US20030206972 ( (2003)
Kanazawa A, Unnaka Y, Wakabayashi T. Unsaturated fatty acid derivativeJPS59222487 (1984)
Fariss M, Smith JD. Anti-tumor activity of vitamin E, cholesterol, taxol and betulinic acid derivatives. EP1189607 (2002)
Sylvester PW, El Sayed KA. Anti-cancer tocotrienol analogues and associated methods. US8268786 (2012)
El Sayed KA, Sylvester PW. Tocotrienol esters. US8969303 (2015)
Gardner R, Hurley L, Israel K, et al. Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof. EP1115398 (2010)

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