How to cite:
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
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Eduvest – Journal of Universal Studies
Volume 2 Number 2, February, 2022
p- ISSN 2775-3735- e-ISSN 2775-3727
MECHANISM OF ACTION OF TUMORIGENESIS OF
ANTICANCER MOLECULES OF PALM OIL
TOCOTRIENOLS (Elaeis guieensis Jacq.): A
SYSTEMATIC REVIEW
Humairah Medina Liza Lubis
1
, Emni Purwoningsih
2
, Annissa Ambaravista
Nasution
3
, Qatrunnada Medina Salim
4
Department of Anatomical Pathology, Faculty of Medicine, Universitas
Muhammadiyah Sumatera Utara, Medan, Indonesia
1
, Department of
Biochemistry, Faculty of Medicine, Universitas Muhammadiyah Sumatera
Utara, Medan, Indonesia
2
, Faculty of Medicine, Universitas Muhammadiyah
Sumatera Utara, Medan, Indonesia
3
, Faculty of Medicine, Universitas
Sumatera Utara, Medan, Indonesia
4
Email: [email protected]
1
, emnipur[email protected]
2
,
3
4
ARTICLE INFO ABSTRACT
Received:
January, 26
th
2022
Revised:
February, 17
th
2022
Approved:
February, 18
th
2022
Palm oil contains vitamin E which comprises two
structurally similar compounds namely tocopherols and
tocotrienols. For many years tocopherols considered the
best therapy in curing disease, but in recent research
advances, tocotrienol has been widely used as a powerful
therapy in several diseases, including cancer. We prepared
this article to review and analyze the role of tocotrienols
from palm oil as anticancer molecules and their mechanism
of action in the process of tumorigenesis based on the
literature from PubMed, Scopus, Science Direct, and
ProQuest databases published from 2011 to 2020, and
according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement. Nineteen
English articles and abstracts according to the inclusion
criteria, systematically reviewed and compiled. The results
showed that tocotrienol acts on intracellular and
extracellular targets involved in cell signaling pathways and
Humairah Medina Liza Lubis, Emni Purwoningsih, Annissa Ambaravista Nasution,
Qatrunnada Medina Salim
Mechanism of Action of Tumorigenesis of Anticancer Molecules of Palm Oil
Tocotrienols (Elaeis Guieensis Jacq.): A Systematic Review 432
suppresses the growth of various malignancies, including
breast, lung, prostate, ovarian, liver, brain, colon,
pancreatic, and myeloma cancers. This literature review
shows that the molecular mechanism of action of
tocotrienols has several advantages, namely a positive
effect on cell proliferation, apoptosis, angiogenesis,
metastasis, and inflammation, which when working
together can function as effective agents in cancer therapy.
The tocotrienol-mediated therapeutic action mechanism
could help clinicians to design new strategies for cancer
treatment.
KEYWORDS
Mechanism Of Action; Tocotrienols; Palm Oil; Therapy;
Cancer
This work is licensed under a Creative Commons
Attribution-ShareAlike 4.0 International
INTRODUCTION
Cancer is a deadly disease with an increasing incidence worldwide (Kashyap et al.,
2017; Kashyap et al., 2018). 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
(Kashyap et al., 2018).
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 (Kashyap et al., 2018; 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
Eduvest – Journal of Universal Studies
Volume 2 Number 2, February 2022
433 http://eduvest.greenvest.co.id
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.
RESEARCH METHOD
The study selection of relevant articles previously published from 2011 to 2020
was obtained from the PubMed, Science Direct, Scopus and ProQuest databases, using
the
-
Articles
and abstracts taken are in English, read, reviewed and arranged systematically.
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.
Humairah Medina Liza Lubis, Emni Purwoningsih, Annissa Ambaravista Nasution,
Qatrunnada Medina Salim
Mechanism of Action of Tumorigenesis of Anticancer Molecules of Palm Oil
Tocotrienols (Elaeis Guieensis Jacq.): A Systematic Review 434
Figure 1. Study selection flowchart
Main Functions of Tocotrienols as Anticancer
Tocotrienolsis a natural form of the vitamin E group, which consists of four
different isomers namely - - - -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 (Figure 2) (Mocchegiani et al., 2014; Mérarchi
et al., 2018; Aggarwal et al., 2019).
Eduvest – Journal of Universal Studies
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435 http://eduvest.greenvest.co.id
Figure 2. Anticancer properties of tocotrienols
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 apoptosis-
inducing 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-
lipid formation and mitochondrial membrane modification and activation of pro-
inflammatory 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.
Tocotrienols
Apoptosis
Cell cycle
arrest
Anti-
angiogenesis
Anti-
metastasis
Anti-
oxidant
Humairah Medina Liza Lubis, Emni Purwoningsih, Annissa Ambaravista Nasution,
Qatrunnada Medina Salim
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 VcaP-
luc 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).
Tocotrienols
DNA damage
Oxidative
stress/radiation
Gene mutation
Tumor
initiation
Tumor
development
PI3/AKT
-Catenin
CSC self renewal
IFN-/IL-12
Dendritic cells
Tumor immunity
1
2
3
Eduvest – Journal of Universal Studies
Volume 2 Number 2, February 2022
437 http://eduvest.greenvest.co.id
Figure 3. Chemopreventive effect of tocotrienols. Oxidative stress or radiation causes
DNA damage and induces genetic mutations thereby promoting tumor development with
CSCs being the tumor trigger population. The pathways occur through: 1. Suppressing
CSCs self-renewal and tumorigenicity through inactivation of the PI3/AKT/b-catenin
pathway; 2. Promote dendritic cell mediated tumor immunity, tocotrienols can facilitate
the elimination of tumor cells in the early stages of tumor initiation and achieve
chemopreventive effects; 3. Tocotrienols inhibit tumor development through blocking
oxidative stress or radiation-induced DNA damage. Image modified from Ling et al.,
2012.
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).
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.
Table 1. Results of clinical research on tocotrienols in various types of cancer
Writer
Study
population
Treatment
Results
Significance
Behery et
al., 2013
Metastatic -
SA
mammary
epithelial
cancer cell
line
-tocotrienols
analogs 10 and
38
Anti-proliferative
activity
Tocotrienols
increase the
level and control
the metastatic of
breast
malignancy
Zhang et
al., 2015
Balb/c
nude mice
inoculated
with
cancer
cells
human
colon
SW620
Tocotrienol-rich
fraction (TRF)
from palm oil
for 6 weeks
TRF significantly
inhibits the growth of
xenografts
The strong
anticancer effect
of TRF is
associated
with Wnt . signal
pathway
regulation
Springett et
al., 2015
Pancreatic
cancer
Vitamin E -
tocotrienols
(VEDT) at a
dose of 200-
3200mg per day
Biological activity, in
the form of apoptotic
induction, was seen to
be significant in
neoplastic cells as
The results are
significant but
require further
clinical research
from VEDT to
Humairah Medina Liza Lubis, Emni Purwoningsih, Annissa Ambaravista Nasution,
Qatrunnada Medina Salim
Mechanism of Action of Tumorigenesis of Anticancer Molecules of Palm Oil
Tocotrienols (Elaeis Guieensis Jacq.): A Systematic Review 438
for 13 days
before surgery
and a single
dose on the day
of surgery
measured by elevated
levels of caspase-3
chemopreventio
n and/or
pancreatic
cancer therapy
Shanmuga
m et al.,
2017
Preclinical
several
types of
cancer
Tocotrienol
Several growth factors
and their receptors
such as
VEGF/VEGFR,
bFGF/FGFR,
angiopoietin, and
hypoxia-induced
factors facilitate the
development of
angiogenesis and are
anti-cancer targets
Tocotrienols
exhibit
prominent anti-
angiogenic
effects in a
preclinical
model of tumor
angiogenesis
Fontana et
al., 2019
resistant
prostate
cancer
(CRPC)
derived
T
T on selmCRPC
(PC3 and
DU145)
-TT provides
cytotoxic/proapoptotic
activity in
CRPC cells
Apoptosis
involves ER
stress and
autophagy
(in autophagy-
positive PC3
cells), and
paraptosis is
involved in anti-
cancer activity
-TT in CRPC
cells.
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.
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