The Study – Prostate Cancer

Prostate cancer is the second most common cancer in men worldwide and the fourth most commonly occurring cancer overall. About 1.3 million new cases were observed in 2018. Other than skin cancer, prostate cancer is the most common cancer in American men. According to the American Cancer Society, estimate for prostate cancer in the United States for 2019 are that about 174,650 new cases of prostate cancer and about 31,620 deaths from prostate cancer. Even in India, prostate cancer is among the top ten leading cancers. About 25,696 new cases were observed in 2018 and 17,184 deaths took place due to prostate cancer. The incidence rates of prostate cancer are constantly and rapidly increasing in India. The cancer projection data shows, that the number of cases in India will be doubled by 2020.

According to American Cancer Society, about 1 man in 9 will be diagnosed with prostate cancer during his lifetime. This cancer develops mainly in older men. About 6 cases in 10 are diagnosed in men aged 65 or older, and it is rare before age 40. The average age at the time of diagnosis is about 66. Moreover, prostate cancer is the 2nd leading cause of cancer death in American men, behind lung cancer. About 1 man in 41 will die of prostate cancer. Speaking of survival rates of people suffering from prostate cancer, if the cancer is localized or regional then 5 – year relative survival rate is nearly 100%, if it is distant then it is around 30%.

In the pursuit to fight cancer, researchers have discovered Tocotrienol which is supposed to exhibit anti-cancer activities. Several studies have been conducted over Annatto based Tocotrienol (DeltaGold – Eannatto).  Several studies have been conducted on Tocotrienol for its effects against prostate cancer like “Annatto Tocotrienol Induces a Cytotoxic Effect on Human Prostate Cancer PC3 Cells via the simultaneous inhibition of Src and Stat 3” where the effects of Delta-Tocotrienol was observed in suppressing cell growth in human prostate cancer (PC3, androgen – independent type) cells via the inhibition of Src and Stat 3.

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. 1: 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.

Study - Annatto Tocotrienol Induces a Cytotoxic Effect on Human Prostate Cancer PC3 Cells via the simultaneous inhibition of Src and Stat 3.

There remains a high level of unmet need in the management of prostate cancer. Actually, the treatment for men who develop androgen – independent prostate cancers is limited to chemotherapy with the taxane docetaxel; however, the treatment output is very poor. It has also been observed that overexpression of a non – receptor tyrosine kinase, Src, during the transition from an androgen – dependent to an androgen – independent state in prostate cancer contributes to a poorer prognosis and reduced overall survival. Src is an integrator of divergent signals, facilitating the action of other oncogenic signal proteins, making it an attractive target for the treatment of several human receptors. In addition, in prostate cancer, androgen – independent prostate cancer cells develop the ability to survive and thrive by stimulating oncogenic pathways that Src regulated. Src inhibitors, currently in phase 3 of clinical trials, are a promising treatment option for patients with androgen – independent prostate cancer.

Signal transducer and activator of transcription (Stat 3), a main downstream target of Src, is frequently activated in several cancer cell lines and tumor tissues and loosely associated with the appearance activated in several cancer cell lines and tumor tissues and closely associated with the appearance of malignancy in several cancers. Among the target genes of Stat 3, some such as cyclin D, Myc, Bcl-xL, and Mcl-1 contribute to oncogenesis by activating the cell cycle and inhibiting apoptosis. In fact, the constitutive activation of Stat3 generates a deregulation of cell growth and survival, invasion of tumor cells and thus the formation of metastasis, and an increase in angiogenesis and suppression of immune surveillance of the tumor. From these reports, it seemed possible that Src inhibitors act as an effective anti-cancer agent for androgen-independent prostate cancer via the inhibition of Stat3. On the other hand, the in vitro and in vivo anti – tumor effects of Src inhibition alone is insufficient in suppressing growth in most cancer cells. In this case, it is considered that the positive effects of Src inhibition are undermined by compensatory pro – survival pathways, especially the Stat3 signal. These reports suggest that the simultaneous inhibition of Src and Stat3 could lead to an effective regulation of androgen – independent prostate cancer cells.

In this study, Annatto Tocotrienol (Eannatto – DeltaGold)was found to act as a potential anticancer agent towards androgen – independent prostate cancer cells (PC3 cells) via the inhibition of Src and Stat3. The Tocotrienol showed cytotoxic effects on PC3 cells in a dose – dependent manner, and the effect depend on G1 arrest in the cell cycle and subsequent induction of apoptosis. In a cytotoxic dose, the Tocotrienol (Eannatto – DeltaGold)suppressed cellular growthvia the simultaneous inhibition of Src and Stat3. Similarly, the treatment combination of both Src and Stat3 inhibitors induced cytotoxic effects in PC3 cells in an additive manner compared to each by itself. With respect to cell cycle regulation and the induction of apoptosis, the combination treatment showed a similar effect to that of the Tocotrienol treatment. These results suggest that Annatto Tocotrienol effectively induces cytotoxicity in androgen – independent prostate cancer cells via the suppression of Src and Stat3.

In other study, in Prostate Cancer, Delta and Gamma-Tocotrienols, in particular, were also shown to inhibit several types of prostate cancer cell lines. While Delta-Tocotrienol (Eannatto – DeltaGold) most effectively induced cell death of prostate cancer cells and activated programmed cell death while disrupting NF-kB signaling, Gamma-Tocotrienol also suppressed prostate cancer in vitro and in vivo. Refer Fig. 2.

Fig. 2: Androgen dependent and Androgen Independent, both kinds of prostate cancers were treated by Delta – Tocotrienol (Eannatto – DeltaGold) and it was observed that Prostate – specific antigen (PSA) was reduced by 40%. Moreover, Delta – Tocotrienol was found effective against both Androgen dependent and Androgen independent prostate cancer.

Summary

So why Tocotrienol?

  • Antioxidants, especially Tocotrienol was observed to exhibit anti-cancer activity against prostate 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. Tocotrienol is a master of anti-angiogenesis in prostate cancer.

    Cancer Angiogenesis
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. Tocotrienol induces apoptosis in cancer cells by increasing endoplasmic reticulum stress and autophagy thus helping in killing cancer cells.
  • Cell Proliferation is the process by which cancer cells copy their DNA and divide into two cancer cells during mitosis and rapidly multiply into more cancer cells. According to several kinds of research, it has been proven that alpha, gamma, and delta Tocotrienols suppress the proliferation of cancer cells.
  • Chemoprevention and anti-cancer activities are some characteristic qualities of Tocotrienol.
  • Chemosensitization is the combination of Tocotrienol with several chemotherapeutic drugs such as celecoxib, statins or dietary components such as curcumin, polyphenols, etc. which effectively sensitize the cancer cells.
  • 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.

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.
  • Tumor nutrition can also be obstructed by Tocotrienol as they may well work on dual antitumor mechanisms that include the removal of the vital nutrient to tumor lifeline.

Dosage

  • According to research, different dosages were used to treat different kind of cancers but no adverse effects were shown up to 3200 mg/day of Tocotrienols while cancer cell death in patients was observed at the dosage of 200-900 mg/day.
  • 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.


Note:

  1. To read studies in detail, follow the references and links given.
  2. The dosages given must not be taken as the advice of a medical practitioner. Consult your physician for the optimum dosage to be consumed.

References:

  • Tocotrienols: Latest Cancer Research in Vitamin E by Barrie Tan, Ph.D., and Anne M.Trias, MS.
  • Tocotrienols: The Promising Analogues of Vitamin Efor Cancer Therapeutics
    https://doi.org/10.1016/j.phrs.2018.02.017
  • World cancer research fund: Americal Institute for Cancer Research
    https://www.wcrf.org/dietandcancer/cancer-trends/prostate-cancer-statistics
  • Annatto Tocotrienol Induces a Cytotoxic Effect on Human Prostate Cancer PC3 Cells via the simultaneous inhibition of Src and Stat 3 by Ryosuke Sugahara, Ayami Sato, Asuka Uchida, Shinya Shiozawa, Chiaki Sato, Nantiga Virgona and Tomohiro Yano.

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