The Study – Leukemia Cancer
About every 3 minutes, one person in the United States of
America is diagnosed with blood cancer. Around 176,200 people in the United
States are expected to be diagnosed with leukemia, lymphoma or myeloma in 2019.
Around 1,399,180 people in the USA are living with, or are in remission from blood
cancer. In every 9 minutes, at least 1 person in the USA dies from a blood
cancer. Around 156 people die each day or more than 6 people die every hour due
to blood cancer in the USA.
For leukemia, around 61,780 people are expected to be
diagnosed with leukemia in the USA.in 2019 and it is estimated that 399,967
people are already living with or are in remission from Leukemia in the USA. The
5 – year survival rate for leukemia is only 61.4% after 5 years as stated in
the report by National Cancer Institute, USA! Very few patients survive for
more than 10 years only due to the common reoccurrence of this cancer.
Conventional treatment modalities for cancer including surgery, radiation, and
chemotherapy have failed to eradicate cancer entirely.
From 2011 to 2015, leukemia was the 6th most common cause of
cancer deaths in both men and women in the USA. Moreover, Leukemia is diagnosed
10 times more often diagnosed in adults than children. Everyday around 150 –
179 Americans are diagnosed with leukemia and 67 lose their battle against it.
Leukemia is the most common cancer in Hispanic children and adolescents. 5 –
year survival rate is around 3% to 4% lower for Hispanics than that of non –
Hispanic whites.
To bring a better solution against such deadly disease,
researchers and doctors have discovered natural anti-oxidants in the form of Annatto
based Tocotrienol(Eannatto – DeltaGold) which can also be used with other
chemotherapeutic drugs that exhibit strong anti-cancer activities and one of
these kinds of research is “Gamma-Tocotrienol and Simvastatin Synergistically
Induce Cytotoxicity In Leukemia Cell Lines, K-562 and HL-60” where it was
observed that Gamma-Tocotrienol, an isoform of Vitamin E, and simvastatin, a
cholesterol lowering drug exhibit synergy in induction of cytotoxicityin K-562
and HL-60 leukemia cell lines. Eannatto has successfully harvested Annatto for
Tocotrienolsrich in Delta – Tocotrienol and Gamma – Tocotrienol to help
Leukemia patients throughout the globe in their fight against blood cancer.
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 - Gamma-Tocotrienol and Simvastatin Synergistically
Induce Cytotoxicity In Leukemia Cell Lines, K-562 and HL-60.
Statins and Tocotrienols regulate the cholesterol
biosynthesis – pathway by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A
(HMG – CoA) reductase. Tocotrienols modulate the 3-hydroxy-3-methylglutaryl
coenzyme A (HMG – CoA) reductaseby post – transcriptional down – regulation. Also,
Tocotrienols contain a farnesol moiety in their side – chain that triggers
degradation of HMG-CoA reductase. These effects lead to suppression of cell
proliferation, cell cycle arrest, and apoptosis. Several studies have shown
that statins have suppressive effects in in vitro experiments on
acute myelocytic leukemia cell lines. Since both statins & Gamma – Tocotrienols(Eannatto
– DeltaGold)are associated with decrease in cholesterol biosynthesis, we
hypothesized that if the cytotoxicity of these drugs on cancer cells is related
to impaired biosynthesis of cholesterol, combination of them may synergize in
cytotoxicity on leukemic cells.
K-562 and HL-60 leukemia cells were grown in Iscove's
Modified Dulbecco's medium with penicillin or streptomycin, 10% fetal bovine
serum and 20% fetal bovine serum were added respectively. K-562 and HL-60
leukemia cells were seeded in 96 well plates, were grown overnight, and treated
for 24 hours, 48 hours and 72 hours with simvastatin in concentrations of 1µM,2µM,4µM,
and 5 µM; Gamma – Tocotrienol(Eannatto – DeltaGold)in concentrations of 20µM,
40µM, and 80 µM; and a combination of the two drugs in the same concentrations.
For the 24 hour dose, cells were seeded at a density of 5000/well and for 48
and 72 hour doses, at 3500/well. Following the treatment, MTS/PMS reagent
(Promega, Madison, WI), [3-(4,5 – dimethylthiazol – 2 – yl) – 5-(3 – carboxymethoxyphenyl)
– 2-(4 – sulfophenyl) – 2H – tetrazolium, inner salt] mixed with and an
electron coupling reagent (phenazinemethosulfate), was added at 40 µg/well and
incubated at 37°C for 2 hours. The solubilized formazan crystals at 450 nm were
measured as an indicator of cytotoxicity. The presence of Adenosine
Triphosphate (ATP) as an indicator of cell viability was measured with the
CellTiterGlo® assay (Promega). Cells were again seeded, grown overnight,
and dosed as mentioned above. Following treatment, the assay was
conducted as specified by the manufacturer.
Both Simvastatin and Gamma – Tocotrienol(Eannatto –
DeltaGold) induced cytotoxicity in K-562 and HL-60 cell lines by the MTS and
Cell Titer Glo Assays. The IC50 at 72 hour incubation were as follows 1)
HL-60: simvastatin - 16.543 uM, gamma tocotrienol - 36.297 uM; 2) K-562:
simvastatin - 5.235 uM, gamma tocotrienol - 34.947 uM. We used CompuSyn
to calculate the IC50. When combined, simvastatin and Gamma – Tocotrienol(Eannatto
– DeltaGold) exhibit synergy at lower concentrations when examined by
isobologram analysis.
Summary
Why Tocotrienol?
Dosage
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Antioxidants, especially Tocotrienol was
observed to exhibit anti-cancer activity against blood cancer cells by lowering
inflammation and oxidative stress as shown in Fig. 2. Also,DeltaGoldTocotrienol(Eannatto
– DeltaGold) has majorly been studied for cancer for 5 years and they have been
observed to reduce inflammation which is quite important since inflammation
encourages tumor growth. Also, Tocotrienols have been observed to reduce
chronic inflammation by decreasing an inflammatory protein connected with
cancer called Nf-kB, as well as other biomarkers. Estrogen-receptor-positive
(ER+) and estrogen-receptor-negative (ER-) both were observed to be reduced by
the action of Tocotrienol by inhibition of HMGCR activity.
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Fig. 2: 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 which is the process of formation
of blood vessels in cancer cells like in your brain cancer. Tocotrienol
promotes cancer cell death to a very great extent and good results of
anti-angiogenesis property of Tocotrienols have been observed against blood
cancer cells in the study.
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Fig. 3: 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. Reports have indicated that
Delta-Tocotrienol and Gamma-Tocotrienol have been observed to induce apoptosis
in leukemia cells in vitro via nuclear chromatin condensation and nuclear
fragmentation. According to studies, it has also been observed that
Gamma-Tocotrienol induced apoptosis in leukemia cells by inhibiting NF-kB,
activating the caspase cascade, increasing cyt.c release and nuclear
fragmentation.
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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. Tocotrienol isoforms have been
observed to suppress cell proliferation.
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Chemoprevention and anti-cancer activity against
Leukemia have been observed in Tocotrienols.
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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. A combination of
simvastatin and Gamma-Tocotrienol induce cytotoxicity and exhibit synergy in
leukemia cells.
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Helps maintain Healthy Cells andremember: when
you think of your health, think of your cells. We have thirty eight trillion of
them! Tocotrienols play an important role in maintaining cellular health which
includes preventing cells from going rancid and aberrant. Tocotrienols could
potentially urn “rancid” and “aberrant” cells back to normal.
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The cytotoxic effect has been observed to be
exerted against human T-cell lymphoblastic leukemia cells by the three isomers
of Alpha-Tocotrienol, Gamma-Tocotrienol, and Delta-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.
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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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Anti-Tumor effects against cancer have been
observed by all kinds of Tocotrienols isoforms.
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Fig. 4: 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.
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Immune System: One study showed that Annatto
Tocotrienol combined with antibiotics had the greatest efficacy in decreasing
bacteria when compared with Tocotrienol or antibiotic treatment alone. This
antimicrobial effect of Tocotrienol was strongly associated with increased
activity of natural killer cells against MRSA, including improved results for
repairing wounds.TakingTocotrienols in this instance would show even stronger
beneficial results for the immune system and its T cells. A study was done with
DeltaGOldTocotrienol to assess T and B lymphocytes in a mitogen – challenge
(toxin pathogen secretes). Delta – Tocotrienol was the strongest in
“Antioxidant Assay” and the fastest in the “Micronutrient
Assay”. Interestingly, Delta – Tocotrienol is complemented by Vitamin C as
vitamins C and E are known to synergize.
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Around 200-900 mg/day of Tocotrienols have been
used to treat different kinds of cancers without any adverse effects and with
good results.
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Substances that complement Tocotrienol for
cancer include Vitamins C, D, Selenium, B complex.
Why Tocotrienol and Not Tocopherol?
References
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Tocopherol, the enemy of Tocotrienol: Tocopherol
interferes with the functioning of Tocotrienol as it attenuates blood 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 targeting more number of blood cancer cells.
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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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Fig. 5: In the first graph, it can be observed that
Tocotrienol uptake is maximum when Alpha – Tocopherol concentration is 0 but as
the concentration of Alpha – Tocopherol increases, the concentration of uptake
of Tocotrienol decreases. While, in the 2nd graph it can be observed that as
the concentration of Alpha – Tocopherol increases in the dosage of Tocotrienol,
the apoptosis induction property of Tocotrienol was suffered and cancer kill
was compromised.
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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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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: The Promising Analogues of Vitamin
E for Cancer Therapeutics
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Gamma-Tocotrienol and Simvastatin
Synergistically Induce Cytotoxicity In Leukemia Cell Lines, K-562 and HL-60
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National Cancer Institute, Cancer Stat Facts:
Leukemia
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