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

Fontana F, Raimondi M, Marzagalli M, Moretti RM, Marelli MM, Limonta P

Recent Pat Anticancer Drug Discov. 2019 Jan 15. doi: 10.2174/1574892814666190116111827. [Epub ahead of print]

Abstract

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 a 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 of 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.

Lim JJ, Wan Zurinah WN, Mouly V, Norwahidah AK

Oxid Med Cell Longev. 2019 Jan 10;2019:9141343. doi: 10.1155/2019/9141343. eCollection 2019.

Abstract

Human skeletal muscle is a vital organ involved in movement and force generation. It suffers from deterioration in mass, strength, and regenerative capacity in sarcopenia. Skeletal muscle satellite cells are involved in the regeneration process in response to muscle loss. Tocotrienol, an isomer of vitamin E, was reported to have a protective effect on cellular aging. This research is aimed at determining the modulation of tocotrienol-rich fraction (TRF) on the gene expressions of stress-induced premature senescence (SIPS) human skeletal muscle myoblasts (CHQ5B). CHQ5B cells were divided into three groups, i.e., untreated young control, SIPS control (treated with 1 mM hydrogen peroxide), and TRF-posttreated groups (24 hours of 50 μg/mL TRF treatment after SIPS induction). The differential gene expressions were assessed using microarray, GSEA, and KEGG pathway analysis. Results showed that TRF treatment significantly regulated the gene expressions, i.e., p53 (RRM2B, SESN1), ErbB (EREG, SHC1, and SHC3), and FoxO (MSTN, SMAD3) signalling pathways in the SIPS myoblasts compared to the SIPS control group (p < 0.05). TRF treatment modulated the proliferation capacity of SIPS myoblasts through regulation of ErbB (upregulation of expression of EREG, SHC1, and SHC3) and FoxO (downregulation of expression of MSTN and SMAD3) and maintaining the renewal of satellite cells through p53 signalling (upregulation of RRM2B and SESN1), MRF, cell cycle, and Wnt signalling pathways.

Zeb A, Khan AA

Front Nutr. 2019 Jan 10;5:137. doi: 10.3389/fnut.2018.00137. eCollection 2018.

Abstract

Dietary oxidized olive oil, alone or in combination with different doses of α-tocopherol, were given to Swiss albino rats for 30 days; in order to determine its role in oxidative stress and fatty liver, induced by the oxidized olive oils. Serum biochemical parameters and hematological indices of blood were analyzed. The liver was analyzed for histopathological changes, lipid peroxidation, and polar triacylglycerols composition. Results revealed that there was a significant decline in the serum total cholesterol, triglycerides, LDL, glucose and ALT; while a significant increase occurred in the serum HDL levels through the supplementation of α-tocopherol in male and female rats. Hematological parameters were almost in the normal reference range in the groups that were fed α-tocopherol, alone or in combination with oxidized oil, while being significantly altered by the oxidized olive oil. There were acute hepatitis and necrosis in the liver with no fatty changes after feeding with oxidized olive oil, along with varying doses of α-tocopherol. Higher amounts of polar compounds were present in female rats (15.2-93.1 μg/g) compared to male rats (12.2-82.3%) that correspond to the supplementation of α-tocopherol in combination with oxidized oil. Lipid oxidation in liver was minimized by tocopherol, while an increase occurred in the accumulation of oxidized lipids in the liver. These findings revealed that tocopherol is beneficial against the oxidized oil induced biochemical and hematological changes and lipid peroxidation but causes fatty accumulation in the liver. Therefore, the role of tocopherol in patients with fatty liver disease may be considered, as tocopherol may increase the chance of survival.

Tamtaji OR, Taghizadeh M, Aghadavod E, Mafi A, Dadgostar E, Daneshvar Kakhaki R, Abolhassani J, Asemi Z

Clin Neurol Neurosurg. 2019 Jan;176:116-121. doi: 10.1016/j.clineuro.2018.12.006. Epub 2018 Dec 8.

Abstract

OBJECTIVE:

This study was conducted to evaluate the effects of omega-3 fatty acids and vitamin E co-supplementation on gene expression related to inflammation, insulin and lipid in subjects with Parkinson’s disease (PD).

PATIENTS AND METHODS:

This randomized, double-blind, placebo-controlled clinical trial was performed in 40 subjects with PD. Participants were randomly allocated into two groups to take either 1000 mg/day of omega-3 fatty acids from flaxseed oil plus 400 IU/day of vitamin E supplements or placebo (n = 20 each group) for 12 weeks. Gene expression related to inflammation, insulin and lipid were quantified in peripheral blood mononuclear cells (PBMC) of PD patients with RT-PCR method.

RESULTS:

After the 12-week intervention, compared with the placebo, omega-3 fatty acids and vitamin E co-supplementation downregulated gene expression of tumor necrosis factor alpha (TNF-α) (P = 0.002) in PBMC of subjects with PD. In addition, omega-3 fatty acids and vitamin E co-supplementation upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.03), and downregulated oxidized low-density lipoprotein receptor (LDLR) (P = 0.002) in PBMC of subjects with PD compared with the placebo. We did not observe any significant effect of omega-3 fatty acids and vitamin E co-supplementation on gene expression of interleukin-1 (IL-1) and IL-8 in PBMC of patients with PD.

CONCLUSIONS:

Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks in PD patients significantly improved gene expression of TNF-α, PPAR-γ and LDLR, but did not affect IL-1 and IL-8.

Aykin-Burns N, Pathak R, Boerma M, Kim T, Hauer-Jensen M

Semin Radiat Oncol. 2019 Jan;29(1):55-61. doi: 10.1016/j.semradonc.2018.10.008.

Abstract

Despite advances in radiation delivery techniques, side effects of radiation therapy due to radiation exposure of normal tissues are common and can limit the deliverable dose to tumors. Significant interests lie in pharmacologic modifiers that may protect against normal tissue toxicity from cancer treatment while simultaneously enhancing the tumor response to therapy. While no such treatments are available in the clinic, this is an area of active preclinical and clinical research. This review summarizes research studies that provide evidence to indicate that tocotrienols, natural forms of vitamin E, are potent radiation protectors and may also have antitumor effects. Hence, several current clinical trials test tocotrienols as concomitant treatment in cancer therapies.

Özgül H, Tatar C1, Özer B, Aydın H, Sarı S, Özer SP

Ulus Travma Acil Cerrahi Derg. 2019 Jan;25(1):1-6. doi: 10.5505/tjtes.2018.30413.

Abstract

BACKGROUND:

Acute pancreatitis is a disease with high morbidity and mortality, despite all the advances in technology. The overall mortality rate of acute pancreatitis is 10%, whereas the mortality rate in infected necrotizing pancreatitis is approximately 35%. In this study, we aimed to establish acute pancreatitis in rats in order to try out the alpha-tocopherol treatment protocol and to reveal the results biochemically and histopathologically.

METHODS:

Twenty-four male male Sprague-Dawley rats weighing between 300 and 350 g were used in the study. In Group 1, 80 µg/kg of normal saline was subcutaneously injected into eight rats; in Group 2, 80 µg/kg of cerulein was subcutaneously injected into eight rats; and in Group 3, 80 µg/kg of cerulein was subcutaneously injected into eight rats. In addition, 30 mg/kg of alpha-tocopherol was intraperitoneally injected into eight rats.

RESULTS:

The mean Schoenberg score, serum amylase, and lipase and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were statistically significantly higher in Group 2 than in Group 1. The mean Schoenberg score and serum amylase and lipase levels were statistically significantly lower in Group 3 than in Group 2.

CONCLUSION:

In this experimental study rat model of cerulein-induced acute pancreatitis, 30 mg/kg of alpha-tocopherol was injected intraperitoneally to examine its effect on pancreatitis. The improvement was observed in the histopathological examination of pancreatic tissues. We think that alpha-tocopherol may have a therapeutic effect on pancreatic tissue.

Griffin JD, Christopher MA, Thati S, Salash JR, Pressnall MM, Weerasekara DB, Lunte SM, Berkland CJ

Mol Pharm. 2019 Jan 7. doi: 10.1021/acs.molpharmaceut.8b00887. [Epub ahead of print]

Abstract

Contemporary approaches to treating autoimmune diseases like Multiple Sclerosis broadly modulate the immune system and leave patients susceptible to severe adverse effects. Antigen-specific immunotherapies (ASIT) offer a unique opportunity to selectively suppress autoreactive cell populations, but have suffered from marginal efficacy even when employing traditional adjuvants to improve delivery. The development of immunologically active antigen delivery vehicles could potentially increase the clinical success of antigen-specific immunotherapies. An emulsion of the antioxidant tocopherol delivering an epitope of proteolipid protein autoantigen (PLP139-151) yielded significant efficacy in mice with experimental autoimmune encephalomyelitis (EAE). In vitro studies indicated tocopherol emulsions reduced oxidative stress in antigen presenting cells. Ex vivo analysis revealed that tocopherol emulsions shifted cytokines responses in EAE splenocytes. In addition, IgG responses against PLP139-151 were increased in mice treated with tocopherol emulsions delivering the antigen suggesting a possible skew in immunity. Overall, tocopherol emulsions provide a functional delivery vehicle for ASIT capable of ameliorating autoimmunity in a murine model.

Mukai K, Ohara A, Ito J, Hirata M, Kobayashi E, Nakagawa K, Nagaoka SI

J Oleo Sci. 2019 Jan 1;68(1):21-31. doi: 10.5650/jos.ess18179. Epub 2018 Dec 12.

Abstract

A kinetic study of the reaction of singlet oxygen (¹O₂) with eight vegetable oils 1-8 containing different concentrations of tocopherols (Tocs) and tocotrienols (Toc-3s) was performed. The second-order rate constants (k_Q) for the reaction of ¹O₂ with vegetable oils 1-8 (rice bran, perilla, rape seed, safflower, grape seed, sesame, extra virgin olive, and olive oils) were measured in ethanol/chloroform/D₂O (50:50:1, v/v/v) solution at 35°C using UV-vis spectrophotometry. Furthermore, comparisons of k_Q values determined for the above oils 1-8 with the sum of the product {∑k_Q^AO-i [AO-i]/10⁵} of the k_Q^AO-i values obtained for each antioxidant (AO-i) and concentration (in mg/100 g) ([AO-i]/10⁵) of AO-i (Tocs and Toc-3s) contained in the oils 1-8 were performed. The observed k_Q values were not reproduced by the k_Q values calculated using only the concentrations of the four Tocs and Toc-3s. These results suggest that the contribution of fatty acids contained in the oils 1-8 is also necessary to fully explain the k_Q values. Recently, the second-order rate constants (k_S) for the reaction of aroxyl radical (ArO・) with the same vegetable oils 1-8 were measured in the same solvent at 25℃ using stopped-flow spectrophotometry (Ref. 23). The k_S values obtained could be well explained as the sum of the product {Σ k_S^AO-i [AO-i]/10⁵} of the k_S^AO-i and the [AO-i]/10⁵ of AO-i (Tocs and Toc-3s) contained in the vegetable oils.

Nobili V, Alisi A, Mosca A, Crudele A, Zaffina S, Denaro M, Smeriglio A, Trombetta D

Antioxid Redox Signal. 2018 Dec 27. doi: 10.1089/ars.2018.7704. [Epub ahead of print]

Abstract

TRIAL DESIGN:

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for paediatric NASH. We performed a randomized double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative-stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and Hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD.

METHODS:

440 consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo, for 4 months.

RESULTS:

Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin-resistance, triglyceride levels, oxidative-stress parameters and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins.

CONCLUSION:

The HXT and vitamin E treatment improved the main oxidative-stress parameters, insulin resistance and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD related liver damage in children.

Nagashimada M, Ota T

IUBMB Life. 2018 Dec 27. doi: 10.1002/iub.1991. [Epub ahead of print]

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. NAFLD manifests as hepatic lipid accumulation, insulin resistance, and inflammation, and can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the underlying mechanisms of NAFLD, including those that drive its progression, are unclear. Both liver-resident (Kupffer cells) and recruited macrophages play a crucial role in the development of insulin resistance and NASH. Therefore, NALFD could potentially be ameliorated by modifying the polarization of macrophages/Kupffer cells. Reactive oxygen species induce oxidative stress, which is implicated in the progression of NASH. Micronutrients, including vitamins, are potent antioxidants that exert anti-inflammatory effects, and are used in the treatment of NAFLD. We review here the molecular mechanisms of the pathogenesis of NAFLD and the potential utility of vitamin E in its prevention and/or treatment.