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.
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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.
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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.
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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.
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So why Tocotrienol?
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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.
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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%.
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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.
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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.
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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.
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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.
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Chemoprevention and anti-cancer activities
are some characteristic qualities of Tocotrienol.
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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.
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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.
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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.
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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
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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.
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Substances that complement Tocotrienol for
cancer include Vitamins C, D, Selenium, B complex.
Why Tocotrienol and Not Tocopherol?
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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.
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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.
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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.
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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.
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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.
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Absorption: As compared to Tocopherols,
Tocotrienols absorb better in the body and Tocopherols have been observed to
prevent absorption of Tocotrienols.
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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.
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Tocotrienols: Latest Cancer Research in Vitamin
E by Barrie Tan, Ph.D., and Anne M.Trias, MS.
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Tocotrienols: The Promising Analogues of Vitamin
Efor Cancer Therapeuticshttps://doi.org/10.1016/j.phrs.2018.02.017
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World cancer research fund: Americal Institute
for Cancer Research
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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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