MECHANISM OF ACTION OF TUMORIGENESIS OF ANTICANCER MOLECULES OF PALM OIL TOCOTRIENOLS (Elaeis guieensis Jacq.): A SYSTEMATIC REVIEW

Humairah Medina Liza Lubis, Emni Purwoningsih, Annissa Ambaravista Nasution, Qatrunnada Medina Salim. (2022). Mechanism of Action of Tumorigenesis of Anticancer Molecules of Palm Oil Tocotrienols (Elaeis Guieensis Jacq.): A Systematic Review. Journal Eduvest. Vol 2(2): 431-440 E-ISSN: 2775-3727 Published by: https://greenpublisher.id/ Eduvest – Journal of Universal Studies Volume 2 Number 2, February, 2022 pISSN 2775-3735e-ISSN 2775-3727


INTRODUCTION
Cancer is a deadly disease with an increasing incidence worldwide (Kashyap et al., 2017;. Based on GLOBOCAN 2018 data, it is estimated that 18.1 million new cancer cases and 9.6 million deaths occurred in 2018. Conventional cancer treatment has focused on chemotherapy and radiotherapy, which sometimes have a detrimental effect on cancer patients. Therefore, the latest research is growing, especially in studying the molecular mechanism of tumorigenesis, as well as the development of new anticancer agents that are safe and effective. In recent decades, one of the main focuses of anticancer research has been on natural agents capable of fighting cancer cells . Palm oil (Elaeis guineensis Jacq.), has been widely cultivated because the oil from the seeds and fruit is very beneficial for the industrial sector and has potential as a medicinal plant. Palm oil is also used as the main source of ingredients for kitchen needs and is widely consumed by people in Asia and Africa. More than 85% of palm oil production is provided by Indonesia and Malaysia as the main producers in the world (Mancini et al., 2015;Absalome et al., 2020).
Palm oil contains vitamin E which is an essential fat-soluble nutrient, obtained from food and supplements. In addition to their antioxidant activity, vitamin E components have the potential to influence various mechanisms underlying human health and disease. Vitamin E consists of two structurally similar compounds namely tocopherols and tocotrienols. The main theory states that tocotrienols have anticancer effects by inhibiting lipid peroxidation, antioxidant activity of tocotrienols can prevent oxidative damage to Deoxyribonucleic acid (DNA) and as a chemopreventive. Administration of tocotrienols in mice, rat, and human tumor cell lines has been shown to inhibit growth cancer cells (Catalgol, Batirel and Ozer, 2011;Bak et al., 2017).
Tocotrienols as a natural compound, it has been observed that it has antioxidant, antiproliferative, pro-apoptotic, anti-inflammatory, antiangiogenic, anti-invasive, and anti-metastatic activity, so it has potential as a chemopreventive or chemotherapeutic agent Mérarchi et al., 2018;Sethi et al., 2018). In addition, the beneficial effects that have been proven are effective in lowering cholesterol levels and as neuroprotective, while in suppressing the growth of malignancies have been studied in the ovaries, liver, stomach, prostate, brain, blood, pancreas, and uterus (Rizvi et al., 2014;Kanchi et al., 2017). In this literature review, we will summarize the latest data showing the unique anticancer effect, discuss the molecular mechanism of action of tumorigenesis of tocotrienols in various cancer models that can prove tocotrienols as promising chemopreventive and chemotherapeutic agents. Because in Indonesia there are so many and easy to find palm oil plants, it must be utilized as best as possible by exploring the possibility of using tocotrienols as a replacement therapy for conventional cancer treatment in Indonesia. Next we will highlight recent advances in the development and testing of tocotrienols-based cancer therapies.
The studies in the selected articles met four inclusion criteria, namely: (1) sources: tocotrienols from palm oil; (2) effect: anticancer; (3) mechanism: acts on intracellular and extracellular targets involved in cell signaling pathways and has been shown to suppress the growth of various malignancies, including breast, lung, prostate, ovarian, liver, brain, colon, pancreatic, and myeloma cancers; (4) results: positive effect on cell proliferation, apoptosis, angiogenesis, metastasis, and inflammation; And articles will be excluded if: (1) palm oil content is not tocotrienols molecules; (2) has an effect on chronic diseases other than cancer (3) irrelevant results.

RESULT AND DISCUSSION
In a literature search we identified 2532 studies. Then 229 duplicate articles were removed and a further 2303 articles were carefully evaluated. Although 280 articles met the inclusion criteria, 261 were excluded because they were not eligible for this study.The number of articles analyzed was 19 articles. The study selection flowchart and reasons for rejection can be seen in Figure 1.

Main Functions of Tocotrienols as Anticancer
Tocotrienolsis a natural form of the vitamin E group, which consists of four different isomers namely α-, β-, γ-, δ-tocotrienols (Peh et al., 2016). Tocotrienols are found in rice bran oil, palm oil and annatto seed (Rashid Khan et al., 2015). Tocotrienols are the main phytonutrients found in palm oil and can be found in the palm oil fraction known as the tocotrienol-rich fraction (TRF) (Subramaniam, Selvaduray and Radhakrishnan, 2019). Various beneficial properties of tocotrienols have been reported in recent years. Tocotrienols act as cellular lipid antioxidants which are effective as anti-inflammatory, antiangiogenic, antiinvasive, and antimetastatic agents that are involved in disease cure and have potential as chemopreventive or chemotherapeutic agents although they have not been clinically tested on a large scale (  Its chemopreventive properties have been studied extensively in a number of animal models. In contrast to the effects of tocopherols on animal models of carcinogenesis (colon, prostate, breast and lung) which often yield inconsistent results, most of the studies on tocopherols have shown positive chemopreventive effects (Ling et al., 2012).

Inhibition of Cell Proliferation and Induction of Apoptosis
Apoptosis is an important process used as an innate defense mechanism against cancer initiation (Marcus et al., 2014). Several in vitro and in vivo experiments have confirmed that apoptosis can induce the potential of natural molecules. Tocotrienols are among several natural compounds with effective antitumor activity through apoptosisinducing pathways. Tocotrienols downregulate the expression of several oncogenic gene products by inhibiting the NF-B pathway and also cause substantial apoptosis in tumor cells (Aggarwal et al., 2019).
Inhibition of proliferation and induction of apoptosis has also been reported to be mediated through tocotrienols-induced activation of the EGR-1/BAX pathway, upregulation of miR-34a125, miR-429135, p27/CDKN1B136 and PPAR-γ137, impaired lipid formation and mitochondrial membrane modification and activation of proinflammatory genes. apoptosis. In addition, tocotrienols and their metabolite 13`-COOH modulate sphingolipid metabolism through inhibition of dihydroceramide desaturase (DEGS). In addition, pathway analysis of tocotrienols-induced gene expression profiling changes showed that -T3 and -T3 alter endoplasmic reticulum stress signaling and associated autophagy and cell death (Yang et al., 2020).

Tocotrienols and Cancer-related Studies
Research about cancer using tocotrienols has been studied extensively in humans. Many studies have shown that lower tocotrienols intake or nutritional status is associated with an increased risk of various types of cancer.

Mechanism of Action of Tumorigenesis of Anticancer Molecules of Palm Oil Tocotrienols (Elaeis Guieensis Jacq.): A Systematic Review 436
Cancer, as it is widely known, is a class of diseases in which cells show uncontrolled growth and can damage surrounding tissues, and can metastasize or spread to other locations in the body via the lymph or blood vessels. Interest in the use of alternative and complementary therapies, especially tocotrienolsas a chemopreventive greatly increased especially for cancer treatment. In this study, chemoprevention by tocotrienols could slow the formation and delay the development of neoplasms. Regulation of signal transduction pathways associated with tumor formation (tumorigenesis) is considered a key point for slowing cancer progression (Catalgol, Batirel and Ozer, 2011). Figure 3 describes the mechanism of the chemopreventive effect of tocotrienols.
Increasing evidence supports the role of tocotrienols in cancer prevention. The theory about the effect of tocotrienols as anticancer is the inhibition of lipid peroxidation and with antioxidant activity it can prevent oxidative damage to DNA (Deng et al., 2019).
Research on vertebral bone metastases from prostate cancer patients using VcaP cell line NCr (-/-) nude mice of eight weeks old male injected subcutaneously with VcaPluc cells in matrigel and given a mixture of tocotrienols for 8 weeks was able to inhibit the growth of prostate tumor xenografts. man. The concentration of tocotrienols and their metabolites increased significantly in the treatment group. Tocotrienols inhibit prostate tumor growth by suppressing cell proliferation, which is associated with cyclin-dependent induction of kinase (CDK) inhibitor p21and p27 (Huang et al., 2017).  In human breast cancer, several effects of tocotrienols have been shown to inhibit the growth of cancer cells. Cells were treated with 50 M Omega 3-docosahexaenoic acid (DHA) and 5 M vitamin E Delta-tocotrienol (Delta-T3) which showed that DHA could trigger an increase in lipid droplet (LD) biogenesis and the combination treatment with Delta-T3 was able to reduce biogenesis. LD. In addition, it was found that higher cytoplasmic LD was associated with higher malignancy and breast cancer cell proliferation (Pizato et al., 2019).

Tocotrienols
Immunotherapy research conducted Hafid and Radhakrishnan (2019) used dendritic cells with a tumor vaccine (DC vaccine) in combination with daily supplementation of TRF to enhance the antitumor immune response potency. DC vaccine immunotherapy together with TRF supplementation induces immunity to tumors. This study used female BALB/c mice induced by breast cancer (Hafid and Radhakrishnan, 2019). Several cancer treatment and prevention studies are summarized in table 1.

CONCLUSION
A wide variety of bioactive compounds isolated from natural products including tocotrienols, have various therapeutic benefits and potential for cancer prevention and treatment. The mechanism of action of tocotrienols at the cellular and molecular levels leads to the modulation of various cancer-associated signaling pathways. The tocotrienols-mediated therapeutic action mechanism could help researchers and clinicians to design new strategies for cancer treatment.