Globally, breast cancer represents one in four of all cases in women. According to a report by WHO, since 2008, worldwide breast cancer cases have amplified by 20%! It is anticipated that worldwide over 508,000 women died in 2011 due to breast cancer. In fact, breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. There were over 2 million new cases in 2018. Currently, the average risk of a woman developing breast cancer sometime in her life is about 12 – 15%. This means there is a 1 in 8 chance she will develop breast cancer. Moreover in recent years, incidence rates have increased by 0.4% per year! Breast cancer is the second leading cause of cancer death in women.
In the chase to fight cancer, researchers have discovered Tocotrienol which has anti cancer properties. Tocotrienols has been derived from plant annatto (DeltaGold – Eannatto). Several studies have been conducted on Tocotrienol for its effects against breast cancer like, ‘miR-429 mediates Delta-Tocotrienol induced apoptosis in triple-negative breast cancer (TNBC) cells by targeting XIAP ‘where the effects of Delta-Tocotrienol on exponentially growing TNBC cells, MDA_MB-231 and MDAMB-468 cells were observed. These cells are also known as human triple negative breast cancer cells which were treated in the presence of Delta-Tocotrienol (DeltaGold – Eannatto) for 24 hours, and the cell feasibility rate was measured using an MTT assay. It was observed that treatment with Delta-Tocotrienol inhibited the production of MDA-MB-231 and MDA-MB-468 cells in a dose-dependent manner. Another study, ‘Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status’ showed the potential anti – proliferative effects of Tocotrienols on the growth of both estrogen – responsive and estrogen – unresponsive (ER+) MCF7 human breast cancer cells and estrogen – unresponsive (ER-) MDA – MB – 231 human breast cancer cells.
Study 1 – miR-429 mediate Delta-Tocotrienol persuaded apoptosis in triple-negative breast cancer (TNBC) cells by targeting XIAP
The large number of etiological factors and the intricacy of breast cancer pose challenges for prevention and treatment. Triple – negative breast cancer (TNBC) is histologically defined as an insidious carcinoma of the breast that lacks staining for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor – 2 (HER2). TNBC is associated with high proliferative rates, early recurrence, and poor survival rates. Much effort has been spent on the study of the biological behavior of TNBC cells to develop effectual treatment strategies.
MicroRNA (miRNAs) is small, non – coding RNAs of 19 – 25 nucleotides in length that are endogenously articulated in mammalian cells. miRNAs post – transcriptionally regulate gene expression by pairing with complementary nucleotide sequence in the 3’ – UTRs of specific target mRNAs. miRNAs are occupied in biological and pathological processes, including cell differentiation, proliferation, apoptosis, and metabolism. miR – 429, a member of the miR – 200 family of microRNAs, was reported to inhibit expression of transcriptional repressors ZEB1/δEF1 and SIP1/ZEB2 and regulate epithelial – mesenchymal transition. It is significantly down regulated in several cancers, including renal cell carcinoma and gastric cancer. Emerging evidence has shown that over – expression of miR – 429 can hinder proliferation and induce apoptosis in human osteosarcoma cancer cell lines.
In this study, it was shown that miR – 429 was up regulated in TNBC cells treated with Delta – Tocotrienol (DeltaGold – Eannatto). Inhibition of miR – 429 may partially rescue the apoptosis induced by Delta – Tocotrienol (DeltaGold – Eannatto) in MDA – MB – 231 cells. It was also observed that the forced expression of miR – 429 was sufficient to lead to apoptosis in MDA – MB – 231 cells. Furthermore, it was identified that X – linked inhibitor of apoptosis protein (XIAP) as one of miR – 429’s target genes.
Human triple-negative breast cancer (TNBC) cells were seeded in 6 – well plates at a concentration of 2×104and cultured in medium without antibiotics for approximately 24 h before transfection. Cells were transiently transfected with miR – 429 precursor or inhibitor and negative control miRNA at a final concentration of 50 nM (precursor) or 100 nM (inhibitor) using Lipofectamine 2000 (Invitrogen, Carslbad, CA, USA) according to the manufacturer’s protocol.
Result
- Delta – Tocotrienol (DeltaGold – Eannatto) was observed to inhibit cell proliferation.
- miR mediated induction of apoptosis in TNBC cells treated with Delta – Tocotrienol.
- Forced expression of miR – 429 induces apoptosis in TNBC cells via suppressing XIAP.
Study 2 – Tocotrienols holds back the enlargement of human breast cancer cells irrespective of estrogen receptor status.
Potential anti – proliferative effects of Tocotrienols on the growth of both estrogen – responsive and estrogen – unresponsive (ER+) MCF7 human breast cancer cells and estrogen – unresponsive (ER-) MDA – MB – 231 human breast cancer cells, and effects were compared with those of Alpha – Tocopherol (alpha T). The Tocotrienol – rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a non – linear dose – response but such that complete suppression of growth was achieved at 8 microg/mL. MDA – MB – 231 cells were also inhibited by TRF but with a linear dose – response such that 20 microg/mL TRF was needed for complete growth suppression. Partition of the TRF into individual Tocotrienols exposed that all fractions could restrain the growth of both ER+ and ER- and of ER+ cells in both the presence and absence of estradiol. However, the Gamma – and Delta – Tocotrienol fractions were the most inhibitory.
Complete inhibition of MCF& cell growth was achieved at 6 microg/mL of Gamma – Tocotrienol/Delta – Tocotrienol (Gamma – T3/Delta – T3) in the absence of estradiol and 10 microg/mL of Delta – Tocotrienol in the presence of estradiol, whereas complete suppression of MDA – MB – 231 cell growth was not achieved even at concentrations of 10 microg/mL of Delta – Tocotrienol. By contrats to these inhibitory effects of Tocotrienols, Alpha – Tocopherols had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA – MB – 231 cell growth. These results confirm studies using other sub – lines of human breast cancer cells and demonstrate that Tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. Inhibition of the growth of breast cancer cells by Tocotrienols could have significant clinical implications not only because Tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth – inhibited in the presence as well as in the absence of estradiol.
Summary
So why Tocotrienols?
- Antioxidants, especially Tocotrienol was observed to exhibit anti-cancer activity against breast cancer cells.
- Angiogenesis which is the process of formation of blood vessels in cancer cells like in your breast cancer. Tocotrienol leads to a cancer cell death to a very great extent.
- Apoptosis is the programmed cell death which leads to the death of cancer cells.
- Cell Proliferation is the process by which cancer cells copy their DNA and divide into more cancer cells during mitosis thus lead to spreading cancer.
- Chemoprevention and anti-cancer activity against breast cancer have been observed in Tocotrienols both in vitro and in vivo researches.
- Phenotypes of breast cancer cells, 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.
- Lipid Raft Disruption is induced by Gamma-Tocotrienol which encourages anti-proliferative activity in breast cancer cells.
- K-Ras, H-Ras, and pERK expressions were observed to be inhibited by Gamma-Tocotrienol which inhibited mammary cancer cell growth.
- In Vitro (Procedure performed outside of a living organism) and In Vivo (Effects of an experiment in a living organism)studies of Tocotrienol have shown anti-cancer activities of Tocotrienol against breast cancer cells.
- 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 Her-2/neu transgenic mice.
- Cancer stem cell death has been observed by the action of Tocotrienols especially Delta – Tocotrienols (DeltaGold – Eannatto).
Dosage
- Under the study, 200-900 mg/day of Tocotrienols were used to treat breast cancer cells and no unfavorable effects were observed and the death of breast cancer cells was witnessed.
- Substances that complement Tocotrienol for cancer include Vitamins C, D, Selenium, B complex.
Why Tocotrienol and Not Tocopherol?
- Tocopherol, the enemy of Tocotrienol: Earlier, in a breast cancer clinical study a mixture of Tocotrienol and Tocopherol was used but then Tocopherol was replaced by Gamma-Tocotrienol because it witnessed interference of Tocopherol in the functioning of Tocotrienol! Tocopherol has been observed to assuage cancer inhibition, inhibits absorption, reduces adipose storage, and compromises cholesterol and triglyceride reduction.
- Tocopherol, the antagonist in breast cancer treatment: Alpha-Tocopherol not only interfered with the functioning of Tocotrienol but also antagonized DHA’s anticancer properties.
- Tocotrienol, the protector of State: Tocotrienol has more mobility than Tocopherol due to its small structure.
- Small structure and less molecular weight: The higher anti-oxidant activity of Tocotrienols is due to their small structure and less molecular weight.
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 Therapeuticshttps://doi.org/10.1016/j.phrs.2018.02.017
- miR-429 mediates Delta-Tocotrienol induced apoptosis in triple-negative breast cancer (TNBC) cells by targeting XIAP
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658948/
- Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status
https://www.ncbi.nlm.nih.gov/pubmed/9625593
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