This document summarizes research on the potential role of oil palm phenolics (OPP) in cancer prevention and treatment. Key points include: 1) OPP have demonstrated antioxidant and anti-inflammatory properties that may help prevent chronic diseases like cancer. Studies in mice and human cells show OPP can protect against cancer progression. 2) OPP have been shown to inhibit the growth of human breast and prostate cancer cells in vitro in a dose-dependent manner. In animal studies, OPP supplementation reduced colon polyps and tumors. 3) The anticancer effects of OPP may be due to their ability to induce apoptosis in cancer cells and affect cell cycle genes and signaling pathways involved in proliferation and metastasis.

1. Review Article
PotentialRole of Oil Palm Phenolics in Cancer Prevention& Treatment
Inaam AbdulKarim
Dr. Smiti Gupta
Department of Nutrition & Food Science, Wayne State University Detroit, MI
The oil palms [Elaeis (from Greek, meaning "oil")] comprise two species of the Arecaceae, or
palm family that are used in commercial agriculture in the production of palm oil. Elaeis
guineensis is native to West and Southwest Africa, found mostly between Gambia and Angola,
while Elaeis oleifera is native to tropical Central and South America. The palm fruit is a rich
source of water-soluble oil palm phenolics (OPP), which consist mainly of phenolic acids [1].
Due to their high redox potential, phenolics which comprise of an aromatic ring, are
important antioxidants, acting as strong reducing agents, metal chelators, singlet oxygen
quenchers and hydrogen donors. It’s antioxidative component helps it to counter the oxidative
stress exerted by high temperature and intense sunlight. In recent research, OPP antioxidant
properties have been shown to be of great importance in overcoming chronic diseases such as
cardiovascular disease and cancer in both mice and also in human [2].
1. Introduction
OPP has been shown to have health benefits based on growing evidence, where it has
been assessed for positive bioactivities. In tumor-inoculated mice, OPP was proven to protect
cancer progression. Microarray studies on the tumours showed differential transcriptome profiles
that suggest anti-tumor molecular mechanisms involved in OPP action [3].

2. Prooxidants such as reactive oxygen species (ROS) are known to play a role in triggering
chronic diseases. An example is the hydroxyl radical that can lead to lipid peroxidation, DNA
bases modification or protein damage, in turn, causing tissue damage, chronic diseases and
ageing. In addition to oxidizing macromolecules such as DNA in the body, they also regulate
gene expression, affecting two well-defined transcription factors, the nuclear factor kappa-B and
activator protein-1, resulting in inflammation. Inflammation thus links oxidative stress with
chronic diseases [4].
OPP has been found to be having a higher antioxidant activity in vitro than of well-
known vitamin antioxidants. There are many other mechanisms through which OPP can exert
their actions than just its antioxidant properties. Phenolics have been reported to demonstrate
anticarcinogenic, antimutagenic, anti-inflammatory, antimicrobial, antiproliferative, antiviral and
vasodilatory actions. Also OPP tend to help in sensitizing tumour cells towards chemotherapy,
and when used together with selected chemotherapeutic agents, it enhances cytotoxicity in
cancer cells [5].
2. Chemical Properties of Oil Palm Phenolics
Phenolic acids are a large family of secondary metabolites having hydroxyl benzoic or
hydroxyl cinnamic structures. They commonly occur as free acids and their glycosides, esters
and bound complexes play an important role in plant resistance to oxidative stress, pathogens,
allelopathy and herbivores, and also help in plant growth regulation [6].
These oil palm phenolics (OPP) consist mainly of phenolic acids, that include three
compounds, p-hydroxybenzoic acid, protocatechuic acid and caffeoylshikimic acid isomers.
Phenolic compounds exhibit a wide range of biological and physiological properties due to their

3. ability to act as antioxidants, free radical scavengers, and chelators of divalent cations. The
antioxidant activity of phenolic compounds is influenced by several factors, reducing potential,
polarity, position and degree of hydroxylation, solubility, and stability of the phenoxy radical.
In Phenolic compound structure, of primary importance in determining their antioxidant activity
is the position and degree of hydroxylation [7]
Figure.1: Chemical Structures of Phenolics Acids Compounds.
Protocatechuic acid p-Hydroxybenzoic acid Caffeoylshikimic acid
C9H10O4 (HOC6H4COOH) (C16H16O8)
p-Hydroxybenzoic Acid, It is used as a chemical intermediate for synthetic drugs and in
pharmaceuticals. Crystalline derivatives of benzoic acid, is a crystalline powder; slightly soluble
in water, soluble in hot alcohol, ether; it has a melting point of between 215 - 217 °C, molecular
weight of 138.12 [g/Mol], and a specific gravity of 1.48. It also contains both hydroxyl and
carboxyl group at para-position, which react with either acid or alcohol [8].
Protocatechuic Acid is an aromatic carboxylic acid containing carboxyl group bonded
directly to benzene ring, is a crystalline organic compound; melting at 122 C (starting sublime at

4. 100 C); boiling at 249 C; slightly soluble in water and has a molecular weight of 154.12
[g/Mol]. It occurs naturally in many plants and resins. It is used pharmacologically as
anticarcinogenic agent that reduces the frequency or rate of spontaneous or induced tumours
independently of the mechanism involved. Caffeoylshikimic acid has a molecular weight of
336.29344 [g/Mol] [6].
3. Anti-Oxidant Properties
Many studies conducted recently have shown that diets containing high amounts of
phytochemicals can provide protection against prooxidant-induced diseases, This is as a result of
photochemical high antioxidant activities. Antioxidants preclude prooxidant-induced tissue
damage by preventing the formation of these prooxidants, by scavenging for the prooxidants or
by promoting prooxidant decomposition. Antioxidants have also been found to be caloric
restriction mimetic, the only intervention known to lengthen the median lifespan of animals [9].
OPP has been shown to display antioxidant properties and confer positive outcomes on
degenerative diseases in various animal models without evidence of causing toxicity. Whether in
healthy or diseased states, the utilization of OPP in the nutraceutical market is, subject to
understanding the molecular mechanisms involved in bringing about the positive benefits
observed [10]. Study have been done to identify the in vivo biological effects and molecular
mechanisms of these compounds during healthy states in three major organs (heart, liver and
spleen) of mouse on a normal diet, via microarray gene expression profiling. It was found that
OPP had great potential in scavenging for the prooxidants and causing them to decompose,
hence reducing the toxicity of oxygen compounds in the body [2].

5. Beside the water-soluble phenolic acid-rich complex, the oil palm (Elaeis guineensis)
also contains an excellent repertoire of antioxidant phytochemicals, many of which are lipid-
soluble antioxidants, such as carotenoids (vitamin A precursors), as well as tocotrienols and
tocopherols (vitamin E isomers) [11].
4. Anticancer Properties
Cancer occurs as a consequence of the accumulation of mutations in genes whose protein
products are important in the control of cell proliferation, differentiation and apoptosis.
Normally, before a person develops a tumour, several cancer-promoting factors have to occur
and with a few exceptions, no one mutation alone is sufficient. The main mechanisms for the
development of cancer involve (a) impairment of a DNA repair pathway, (b) the mutation of a
tumour suppressor gene, (c) the transformation of a normal gene (the proto-oncogene) into an
oncogene or (d) mutations in genes involved in apoptotic control [12].
In a study carried to assess the anticancer properties of oil palm phenolics, human breast
and prostate cancer cells were cultured in vitro either in the presence or absence of various doses
(weight %) of palm phenolics. It was that the palm phenolics inhibited the growth of human
cancer cells in a dose dependent manner whereas breast and prostate cancer cells that were not
supplemented with palm phenolics continued to proliferate and grow [13].
In another study that used animal model (rat), Dimethyl hydrazine (DMH) was used as
the chemical trigger, to induce colon carcinogenesis in the rats through multiple doses of DMH
intra-gastrically. The drinking water of the experimental group of animals was supplemented
with palm phenolics, whereas the control group of animals was provided water and not
supplemented with any palm phenolics. All rats were maintained on normal rat chow for the

6. duration of the trial. Rats that had their water supplemented with the palm phenolics
demonstrated significantly lower colon polyps and tumors compared to the control animals not
supplemented with these palm phenolics [14].
4.1. Effect on Apoptotic Pathways
An important mechanism of cytotoxicity in the prevention and treatment of cancer is the
apoptosis or programmed cell death pathway. Apoptosis is characterized by several
morphological and biochemical changes including blebbing of plasma membrane, condensation
of cytoplasm and nucleus, as well as degradation of DNA. The inability of cells to undergo
apoptosis is a key factor in the pathogenesis of malignancies [15].
Recently, there has been increasing interest in the use of palm oil and other oil palm
components in tumor inhibition and regression. In this study, the authors determined the effects
of water-soluble OPP on tumor and normal cell lines, and further checked for the mechanism of
cell death caused by OPP in cell lines which were inhibited by the extract. They also determined
the in vivo effects of OPP on J558 myeloma tumor growth in syngeneic BALB/c mice [16].
Apoptotic cells were detected using a calorimetric detection system in all tumor cells
treated with OPP. There was an increase in the number of apoptotic cells in groups incubated
with higher concentrations of OPP. There were no apoptotic cells detected in normal and
untreated cells. This was found to be consistent with the results of the DNA fragmentation assay
[17].
Isolation and concentration of the phenolics from this palm oil result in OPP. In vitro
exposure of tumor cells to various concentrations of OPP revealed there was a dose dependent
growth arrest and cell death effects of the extract. In the dose experiments, when estrogen

7. receptor positive human breast adenocarcinoma (MCF7), human lung carcinoma (A549) and
mouse IgA-secreting myeloma (J558) cell lines were incubated with difference doses of OPP, the
extract showed a distinct inhibitory effect on the viability and proliferation of the cells at all
doses [18].
These findings are concurrent with the studies on palm oil vitamin E (tocotrienol-rich
fraction) tested on human breast cancer cells, where similar inhibitory actions were reported The
accelerated decrease in the viability of the carcinoma cells started after 24 hours of treatment
with the extract, and was highest at the end of the incubation periods. This effect was more
pronounced with higher concentrations of OPP [10]. In contrast, OPP was shown to enhance the
growth and proliferation of normal vertebrate and invertebrate cell lines in a dose-dependent
manner. Enumerated by the MTT assay, OPP doses below 2000 μg/ml were found to enhance the
growth of the C6/36, BHK and MDCK cell lines. However, cell viability decreased dramatically
after day 7. This could be due to lack of nutrients or space for cell growth [14].
In general, cell death can occur by either necrosis or apoptosis (programmed cell death).
To determine the cell death mechanism of the tumor cells, two methods of detecting DNA
fragmentation were used. Nuclear fragmentation was detected in all samples of tumor cells
treated with various concentrations of OPP, indicating that OPP had induced apoptosis in these
cells in vitro [17]. These results were further confirmed using the TUNEL assay, which showed
that the intensity of cells undergoing apoptosis was greater with higher concentrations of OPP
used. The selective induction of cell death in tumor cells could be due to the presence of gallic
acid in OPP. Agrawal in another study also showed that the tocotrienol-rich fraction of palm oil
activated on p53, resulting in DNA fragmentation and ultimately apoptosis [19].

8. 4.2. Effect on Inflammatory Pathways
12-O-tetradecanoylphorbol-13-acetate (TPA) is diester of phorbol and a potent tumor
promoter often employed in biomedical research to activate the signal transduction enzyme
protein kinase C (PKC). TPA effects on PKC result from its similarity to one of the natural
activators of classic PKC isoforms, diacylglycerol. In animal models, palm oil has been shown to
offer a significant protection against 12-O-tetradecanoyl-phorbol-13- acetate-mediated skin
tumorigenesis in Swiss albino mice [9].
Using Illumina microarrays, It was found that the atherogenic diet induced inflammation,
oxidative stress and increased metabolite turnover of cells in the spleen, liver and heart. On the
other hand, OPP showed signs of attenuating these effects. It increased response of unfolded
proteins in the liver, attenuated antigen presentation and processing in the spleen and up-
regulated antioxidant genes in the heart. Current quantitative reverse transcription-polymerase
chain reactions, validated then the fold changes observed in the microarray gene. While serum
cytokine profiling showed that OPP attenuated inflammation by modulating the Th1/Th2 axis
toward the latter [2].
The most invasive cancers normally produce the broadest spectrum and the highest levels
of chemokines. An important example of a cytokine receptor pair involved in cancer invasion
and metastasis is Cxcl12/Cxcr4. In vitro, the CXCL12 ligand stimulated breast cancer cells to
carry out invasive, including pseudopodial protrusion, directed migration and penetration of
extracellular matrix barriers. In vivo, metastasis to CXCL12-rich lung tissue was blocked in
animal models by treatment with a neutralizing anti-human CXCR4 monoclonal antibody.
Cxcl12 is an important mediator of advanced cancer and contributes significantly to the lethal

9. phenotype. In the present study, the down-regulation of Cxcl12 in tumours was observed in OPP-
treated mice resulting to reduction in invasiveness and metastatic potential of these tumours [5].
Interleukin-12 (IL-12) is a heterodimeric cytokine produced mostly by phagocytic cells in
response to foreign bodies, and to some degree by B lymphocytes. IL-12 induces cytokine
production, primarily of IFN-gamma, from NK and T cells. It acts as a growth factor for
activated NK and T cells, enhancing the cytotoxic activity of NK cells, and favors cytotoxic T
lymphocyte generation. It is demonstrated that OPP cause significant decrease in pro-
inflammatory interleukin [IL-12] and a significant increase in anti-inflammatory interleukin-13,
resulting in control of inflammation [13].
4.3. Effect on Epigenetic Control
Furthermore, genes that are normally associated with cancer proliferation and invasion
such as signal transducer and activator of transcription 3 (Stat3) and chemokine (C–X–C motif)
ligand 12 (Cxcl12) were also down-regulated by OPP. Stat3 signalling is oncogenic and is
required for the transformation of various primary cancer and tumour derived cell lines. As,
many cancer-derived cell lines that constitutively contain activated Stat3 are dependent on this
protein, so when they are treated with antisense or dominant negative constructs directed at
Stat3, they undergo growth arrest or even apoptosis [18].
Niu also showed that blocking Stat3 in cancer cells up-regulates the expression of p53,
leading to p53-mediated tumour cell apoptosis. In addition, inhibition of constitutive Stat3
activity in haematopoietic malignancies such as non-Hodgkin’s lymphoma and multiple
myeloma sensitizes these resistant cancers to chemotherapeutic drug-mediated apoptosis, as well
as suppresses the growth of prostate and astrocytoma cancer cells [20]. To support this,

10. Resveratrol, which has been reported to have anti-tumour properties, has also been found to
inhibit Stat3 signalling in transforming mouse fibroblasts as well as human prostate, pancreatic
and breast carcinoma cell lines [18].
4.4. Effect On Cell Cycle
Functional analysis carried out using microarray data obtained from tumours of mice
indicated that genes involved in the cell cycle were differentially expressed in the OPP-treated
group. Genes such as cyclin A2 (Ccna2), cyclin B1 (Ccnb1), polo-like kinase 1 (Plk1), mitotic
arrest deficient 2, homologue-like 1 (Mad2l1), cell division cycle 20 homologue (Cdc20),
histone deacetylase 6 (Hdac6) and minichromosome maintenance deficient 6 (Mcm6) were
down-regulated by OPP. On the one hand, genes such as cyclin D2 (Ccnd2), cyclin E2 (Ccne2),
cyclin-dependent kinase 4 (Cdk4) and cyclin-dependent kinase 2 (Cdk2) were up-regulated by
OPP [8].
In Ccne2 and Ccna2 genes, obtained from real-time qRT-PCR, the directions and fold
changes for two genes was comparable with those obtained using the microarray technique, thus
validating the microarray results obtained. The regulation of cell-cycle genes found in the present
study suggests that OPP may inhibit tumour growth in vivo by inducing a G1/S phase arrest in
the cell cycle. This is consistent with observations made in several cancer cell lines, in which
cell-cycle arrest was brought about by other phenolic antioxidants such as phenolic acids,
hydroxytyrosol, resveratrol, piceatannol, genistein and luteolin [21].
The opposite direction of regulation of these genes by OPP indicates that, OPP may help
sensitize tumour cells towards chemotherapy, and this might be vital when used together with
selected chemotherapeutic agents for enhanced cytotoxicity in cancer cells [1].

11. 5. Summary.
The burden of chronic diseases is rapidly increasing worldwide. Oxidative stress is a
unifying mechanism in the aetiology of many chronic diseases, including cancer. As such,
dietary antioxidants such as widespread plant phenolics may be important for the prevention and
treatment of chronic diseases. The discovery that the aqueous stream of the oil palm milling
process contains potent phenolics, has raised the possibility that a major disposal liability can be
turned into beneficial use against chronic disease processes [12].
As palm oil contains a rich mixture of phenolic compounds with potent antioxidant and
radical scavenging activity, it is suggested its use may play a vital role in the prevention and
treatment of many of those chronic illnesses that come as a result of cell damage from the
prooxidants. It is widely reported of the capacity of palm oil to modulate the effect of oxidative
stress on serum and antioxidant enzymes in membranes of liver and kidney, oxidative stress
hypertension, suppress pre-neoplastic mammary epithelial cell proliferation, inhibit diesel-
exhaust induced lung tumorigenesis, inhibit tumour promotion as well as modulate the immune
system [22].
As the transformation of normal cells to malignant cells is brought about by, spontaneous
mutation during daily cell division or may be induced by: chemical carcinogens; physical
carcinogens; viruses. If these two factors can be prevented or be inhibited, then it will be possible
to use oil palm phenolics to greatly reduce the incidence of cancer and other chronic diseases [5].
Experiments have been carried out and have shown that cancer being as a result of
uncontrolled growth and spread of abnormal cells, the regulation of cell-cycle genes inhibits
tumour growth, also the prevention of inflammatory pathways can be protective. As OPP have
all the above properties, hence is the way to go in fighting off cancer [2].

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