The Study – Liver Cancer

The increase in incidence of Liver cancer cases has astonished everyone. Since 1980, the incidence of liver cancer has tripled and in between 2006 and 2015, the total number of people diagnosed with Liver Cancer increased by approximately 3% annually. Moreover, men are about 3 times more prone to this disease as compared to women. This year, it has been estimated that 42,030 adults with 29,480 men and 12,550 women in the United States will be diagnosed with primary liver cancer. This data clearly suggests that men are about 3 times more likely than women to be diagnosed with the disease.

It is also estimated that 31,780 people including 21,600 men and 10,180 women will die from these disease this year. In fact, Liver cancer is the 5th most common cause of cancer death in men and in women, it is the 7th most common cause if cancer death among women. Moreover, the overall death rate has more than doubled from 1980 to 2016. Although, Liver cancer is more prominent in sub – Saharan Africa and South – East Asia. Furthermore, the general 5 – year survival rate of people suffering from Liver cancer is 18%. Elaborating on the survival rate even further, it has been found that 44% people who are diagnosed at an early stage, the 5 – year survival rate is 31%. If the cancer has spread to surrounding tissues or organs and/or the regional lymph nodes, the 5 – year survival rate is 11%. If the cancer has spread to a distant part of the body, the 5 – year survival rate is 2%. Henceforth, it can be concluded that Liver Cancer is one the deadliest cancers.

Also, a disease Non – Alcoholic fatty liver disease (NAFLD) is defined as the accumulation of excessive fat in the liver in the absence of excessive drinking of alcohol and any secondary cause. This disease can progress slowly from simple Non – Alcoholic Steatosis (NAS) to Non – Alcoholic Steatohepatitis (NASH) and subsequently to hepatitis fibrosis, cirrhosis of liver and cancer. At present, there is no specific test which can predict progression of NAS to NASH. 

Fig. 1: Stages of Liver Cancer: Liver is very intolerant towards fat. Over 5% fat as shown in the 3rd image of liver is already a very fatty liver.

DeltaGold Tocotrienol against Liver Cancer

Although, researchers have kindled some hope by discovering Annatto based Tocotrienols (DeltaGold – Eannatto) which has been observed to inhibit certain anti – cancer activities against Liver cancer like Apoptosis, Anti – Angiogenesis, Anti – Cell Proliferation, and so on. Several studies on Annatto based Tocotrienols (DeltaGold – Eannatto) have been conducted which have further showed the anti – cancer effects of DeltaGold. One study, “Gamma-Tocotrienol treatment increased peroxiredoxin-4 expression in HepG2 liver cancer cell line” was conducted to observe the effects of Tocotrienol on liver cancer. In the study, it was observed that Tocotrienol inhibited anti-proliferative abilities against liver cancer cells.  In another study related to fatty liver, “Tocotrienols for normalization of hepatic echogenic response in nonalcoholic fatty liver: a randomized placebo – controlled clinical trial” showed hepatoprotective effects of Tocotrienols in hypercholesterolomic adults with Non – Alcoholic fatty liver disease (NAFLD).

Most research in the past 50 – 60 years has been focused on Tocopherols and 50% of all the research in last 30 years has been done on Tocotrienols in last 5 years. Half of the Tocotrienol research ever published has been published in last 10 years as shown in Fig. 1. Each day it is becoming increasingly understood that Tocotienols (especially Eannatto – DeltaGold) are the right form of Vitamin E. Well in excess of 100 studies and clinical trials have shown the surprising benefits of Tocotrienols – without any known side effects.

Fig. 2: In the graph, as you can see, R & D on Tocotrienol has increased exponentially over the years in all fields while research on Tocopherols has decreased. Whether it is cancer, Cardiovascular diseases (CVD), Diabetes, Anti – Oxidant activities or others, in all fields research on Tocotrienol has not only gained pace but quant as well.

So why Tocotrienol?

  • Antioxidants, especially Tocotrienol was observed to exhibit anti-cancer activity against liver cancer cells by lowering inflammation and oxidative stress as shown in Fig. 3.
Fig. 3: In the study conducted by Dr. Qureshi, he saw that at 250 mg of Tocotrienols, the endogenous anti-oxidant, TAS (represented with grey colour) increased, while the C-reactive protein (CRP) dropped by 40%, oxidized fat (MDA) dropped by 34% and Total Anti-oxidant increased by 22%.
  • Angiogenesis or formation of blood vessels in cancer cells promotes cancer cell growth to a very great extent. Gamma-Tocotrienol has also been observed to block the activation of a critical pathway (STAT3) in the survival and angiogenesis of cancerous liver cells.
Fig. 4: In a study, it was observed in mice cells, that Delta – Tocotrienol inhibited the formation of blood vessels in cancer cells (Anti – Angiogenesis) while Tocopherol completely failed on such grounds. Delta-Tocotrienol was also observed to induce apoptosis in the mice cancer cells.
  • Apoptosis or programmed cell death is the process of elimination and death of cancer cells. Gamma-Tocotrienol has been observed to display apoptotic functions in hepatocellular carcinoma (HCC) by upregulation of Bax, caspase-8, and caspase-9; increasing Bid fragmentation; inhibiting STAT3 and its regulated gene products including Bcl-2, Bcl-xL, survivin, cyclin D1, Mcl-1, and VEGF.
  • Cell Proliferation is the process by which cancer cells copy their DNA and multiply into more cancer cells and thus leading to the spreading of cancer. Delta Tocotrienol has been observed to possess maximum anti-proliferative characteristics against HCC cells by upregulating peroxiredoxin-4. Although other isoforms of Tocotrienol also were observed to have commendable anti-proliferative characteristics.
  • Chemoprevention and anti-cancer activity against liver cancer have been observed in Tocotrienols.
  • Hepatocarcinogenesis was observed to be attenuated by the administration of Tocotrienol induced by diethylnitrosamine (DEN) or 2-acetylaminofluorene (AAF) in rats.
  • HCC development mouse xenograft was also observed to be inhibited by the administration of Delta and Gamma Tocotrienols.
  • Lipid-lowering function in HCC was also observed by Gamma-Tocotrienol which may play a role in its anti-cancer activity.
  • Weight loss was observed by the action of Delta – Tocotrienol (DeltaGold – Eannatto). A loss of 9.7 lbs in weight was observed in the patients suffering from diabetes and Non – Alcoholic Fatty Liver Disease.
  • Body Mass Index (BMI) was made better by the effect of Delta – Tocotrienol (DeltaGold – Eannatto). Like BMI from 30.7 was bought to the value 29.9 in 3 months.
  • Triglycerides were reduced by the effect of Delta – Tocotrienol (DeltaGold – Eannatto) by a whopping 9.9% in just 3 months!
  • Liver Enzymes like Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) were lowered by 15.6% and 14.6% respectively by the action of Delta – Tocotrienol (DeltaGold – Eannatto). Lowering of ALT and AST is very necessary for the treatment of Non – Alcoholic Fatty Liver Disease.
  • C – Reactive Protein (hsCRP) was oxidized and lowered by 18% in 3 months by Delta – Tocotrienol (DeltaGold – Eannatto) which is also very necessary for the treatment of Non – Alcoholic Fatty Liver Disease.
  • MDA was also reduced by 14.3% in 3 months by Delta – Tocotrienol (DeltaGold – Eannatto).
  • Fatty liver index was also reduced by a whopping 11.1% by Delta – Tocotrienol (DeltaGold – Eannatto) which was the most spectacular feature of DeltaGold during the treatment of the diseases.
  • Anti-Tumor effects on breast cancer have been observed by all kinds of Tocotrienols isoforms.
  • Annatto-Tocotrienol which comprises of 90% of Delta-Tocotrienol and 10% of Gamma-Tocotrienol reportedly delayed the development of mammary tumor and reduced the number and size of the tumor via enhancing both apoptosis and senescent-like growth arrest in transgenic mice.
  • Cancer stem cell death has been observed by the action of Tocotrienols especially Delta – Tocotrienols (DeltaGold – Eannatto). Even after chemotherapies, radiation and surgeries, there are stem cells of those cancerous tissues left revolving in your body which can lead to your cancer coming back. Henceforth, their death is very necessary and Tocotrienols have been observed to kill cancer stem cells thus preventing further damage to liver again.
Fig. 5: About 1% of cancer cells are Cancer Stem Cells (CSC) which keep circulating in your body even after nailing the cancer through chemo. It has been observed that Gamma – Tocotrienol and Delta – Tocotrienol, both specifically target CSC.

Study 1 – Gamma-Tocotrienol treatment increased peroxiredoxin-4 expression in HepG2 liver cancer cell line.

This study was conducted to determine the Anti – proliferative effects of Gamma-Tocotrienol (DeltaGold – Eannatto) treatment on differential protein expression in HepG2 cells. Under this study, HepG2 cells were treated with 70 μM Gamma-Tocotrienol (DeltaGold – Eannatto)  for 48 hours and differentially expressed protein spots were determined by two-dimensional electrophoresis (2DE), identified by MALDI-TOF mass spectrometer (MS) and validated by quantitative real-time polymerase chain reaction (qRT-PCR).

It was observed that Gamma-Tocotrienol (DeltaGold – Eannatto) treatment on HepG2 cells showed a total of 5 differentially expressed proteins which when compared to their respective untreated cells where three proteins were down – regulated and two proteins were up – regulated. One of these up – regulated proteins was identified as peroxiredoxin – 4 (Prx4) and validation by qRT – PCR however showed decreased expression of Prx4 mRNA in HepG2 cells following GTT treatment. 

Study 2 – Tocotrienols for normalization of hepatic echogenic response in nonalcoholic fatty liver: a randomized placebo – controlled clinical trial.

Non – Alcoholic fatty liver disease (NAFLD) is one of the commonest liver disorders. Obesity, oxidative stress, insulin resistance and lipid peroxidation have been identified amongst the possible hits leading to the onset and progression of this disease. Nutritional evaluation of NAFLD patients have shown a lower – than – recommended intake of Vitamin E. Vitamin E consists of 8 isoforms, 4 Tocopherols and 4 Tocotrienols, Alpha – Tocopherols have een widely investigated in liver diseases, whereas no previous clinical trial has investigated Tocotrienols for NAFLD. The objective of the study was to determine the effects of mixed Tocotrienols, in normalizing the hepatic echogenic response in hypercholerterolaemic patients with ultrasound – proven NAFLD.

87 untreated hypercholesterolaemic adults with ultrasound – proven Non – Alcoholic fatty liver disease (NAFLD) were enrolled and randomized into control group (n = 44) and Tocotrienols group (n = 43). The treatment, either mixed Tocotrienols 200 mg twice daily or placebo, had a 1 – year duration.

Normalization of hepatic echogenic response, being the trial primary aim, was used in sample size calculations. The data were assessed according to treat principle as primary outcome. Per protocol analysis was also carried out as secondary outcome measurement.

30 and 34 participants concluded the study in the Tocotrienols and placebo group respectively. Alpha – Tocopherol levels were within the normal range for all subjects. As primary outcome, the normalization of hepatic echogenic response was significantly higher for the Tocotrienols treated group compared to the placebo group in the intention of treat analysis (P = 0.039; 95% CI = 0.896 – 6.488). As secondary objective, the per protocol assessment also showed significant rate of remission (P = 0.014; 95% CI = 1.117 – 9.456). Worsening of Non – Alcoholic fatty liver disease (NAFLD) grade was recorded in two patients in the placebo group, but none in the group treated with Tocotrienols. No adverse events were reported for both groups. This was the first clinical trial that showed the hepatoprotective effects of Tocotrienols in hypercholesterolemic adults with Non – Alcoholic fatty liver disease (NAFLD).

Summary

Dosage

  • Approximately, 200-900 gms/day of Tocotrienols have been used to treat cancers without any adverse effects and with satisfactory results.
  • In the studies it was observed that 150 mg of Delta – Tocotrienols (DeltaGold – Eannatto) was optimum for a normal person while those suffering from Non – Alcoholic Fatty Liver Disease (NAFLD) were given 250 – 300 mg twice a day which makes around 500 – 600 mg per day.
  • Substances that complement Tocotrienol for Non – Alcoholic Fatty Liver Disease (NAFLD) include CoQ10, Omega – 3, Methionine, Glutathione.
  • Substances that complement Tocotrienol for cancer include Vitamins C, D, Selenium, B complex.

Why Tocotrienol and Not Tocopherol?

  • Tocotrienol the unappreciated Vitamin E: Since several decades, the majority of research has been focused on alpha-tocopherol whereas only 3% of the study has been conducted on Tocotrienol. However clinical studies have significantly proven that Tocotrienols display stronger anti-oxidant, anti-inflammatory, and chemopreventive activities than Tocopherol based Vitamin E.
  • Small structure and less molecular weight: The higher anti-oxidant activity of Tocotrienols is due to their small structure and less molecular weight which assist in their integration of the cell, unlike Tocopherols.
  • Tocopherol in your food: The amount of antioxidants like Tocopherols required by your body is already present in our daily diet so we won’t get any benefit from Tocopherol supplementation.
  • Tocopherol, the enemy of Tocotrienol: Tocopherol interferes with the functioning of Tocotrienol as it attenuates cancer inhibition, inhibits absorption, reduces adipose storage, and compromises cholesterol and triglyceride reduction.
  • Tocotrienol, the protector of State: Tocotrienol has more mobility than Tocopherol due to its small structure so it can cover a larger area and target more cells.
  • Absorption: As compared to Tocopherols, Tocotrienols absorb better in the body and Tocopherols have been observed to prevent absorption of Tocotrienols.
Fig. 6: The 2nd pie chart represents Palm Tocotrienol rich fraction with 32% Alpha – Tocopherol which was given to people and when the Alpha – Tocopherol was removed then it was represented by the 1st pie chart with 0.3% Alpha – Tocopherol which was then given to people. In the graph, the hollow bar represents the Tocotrienol with Tocopherol which reduced the concentrations of Alpha, Gamma and Delta Tocotrienol in the body but when Tocopherol was removed from the dosage (Solid grey bars in graph), the concentrations of Alpha, Gamma and Delta – Tocotrienol significantly increased.

References

  • Tocotrienols: The Promising Analogues of Vitamin E for Cancer Therapeutics

https://doi.org/10.1016/j.phrs.2018.02.017

  • Annato: Delivering Tocotrienols from Amazonia, by Barrie Tan, Founder, &Anne Trias, Product Director

www.nutraceuticalsworld.com

  • Gamma-Tocotrienol treatment increased peroxiredoxin-4 expression in HepG2 liver cancer cell line by Abdul Rahman Sazli F, Jubri Z, Abdul Rahman M, Karsanu SA, Md Top AG, Wan Ngah WZ.

https://www.ncbi.nlm.nih.gov/pubmed/25886747

  • net. Liver Cancer: Statistics.

https://www.cancer.net/cancer-types/liver-cancer/statistics

  • Tocotrienols for normalization of hepatic echogenic response in nonalcoholic fatty liver: a randomized placebo – controlled clinical trial by Enrico Magosso, Mukhtar Alam Ansari, Yogheshwaran Gopalan, Ibrahim Lutfi Shuaib, Jia – Woei Wong, Nurzalina Abdul Karim Khan, Mohamed Rizal Abu Bakar, Bee – Hong Ng, and Kah – Hay Yuen.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877967/

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