Journal of Ethnopharmacology 229 (2019) 54–72

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Review

Are polyphenol antioxidants at the root of medicinal plant anti-cancer T

success?
⁎
A.B. Oyenihi, C. Smith
Dept Physiological Sciences, Stellenbosch University, Private Bag X1, Matieland, Stellenbosch 7602, South Africa

A R T I C LE I N FO A B S T R A C T

Keywords: Ethnopharmacological relevance: Given the severe side effects associated with most of the conventional cancer
Prooxidant medications, as well as the expanding body of evidence indicating secondary toxicity of these drugs, individuals
Alkaloid with cancer are increasingly turning to natural alternatives. Similarly, the pharmaceutical industry is in search of
Oxidative stress natural products to treat cancer. An understanding of the specific active components in plant products with
Plant characterisation
which anti-cancer efficacy is achieved is required for this research to move forward.
Aim of the study: To integrate data from cancer-relatestudies on plant-derived products or extracts, to elucidate
whether these products may have similar active ingredients and/or mechanisms of action, that can explain their
efficacy. This review also includes a discussion of the methodological complexities and important considerations
involved in accurate isolation and characterisation of active substances from plant material.
Conclusions: From the literature reviewed, most plant products with consistently reported anti-cancer efficacy
contains high levels of polyphenols or other potent antioxidants and their mechanisms of action correlate to that
reported for isolated antioxidants in the context of cancer. This suggests that natural products may indeed
become the panacea against this chronic disease – either as therapeutic medicine strategy or to serve as tem-
plates for the design of novel synthetic drugs. The recommendation is made that antioxidant activity of plant
actives and especially polyphenols, should be the focus of anti-cancer drug discovery initiatives. Lastly, re-
searchers are advised to exploit current techniques of chemical compound characterisation when investigating
polyphenol-rich plants to enable the easy consolidation of research findings from different laboratories.

1.Introduction
Cancer remains a significant threat in terms of both morbidity and
mortality as its incidence continues to escalate (Siegel et al., 2017).
Despite efforts aimed at increasing awareness, early diagnosis and novel
therapeutic interventions, the occurrence of drug resistance, elevated
costs of treatment as well as an upsurge in reports of secondary toxicity
of anti-cancer drugs have hindered progress made (Niraula et al., 2014;
Singh et al., 2016). Furthermore, commonly known adverse drug re-
actions (ADR) associated with current chemotherapeutic drugs for ex-
ample, nausea, vomiting musculoskeletal pain, headache, gastritis,
anorexia, oral ulceration, constipation, diarrhoea, alopecia, neuropathy
etc (Singh and Singh, 2018), require additional treatments which fur-
ther increases the overall cost of therapy. Due to these concerns, many
patients in developing and developed countries depend on plant ex-
tracts and phytochemicals to combat cancer. A popular lay consensus
seems to be that plant extracts are safer and more effective than con-
ventional ‘western’ medicine, given the history of their uses to manage
cancers in the ancient medical practices of especially Africa and Asia
(Shukla and Mehta, 2015). While some of these claims have been ex-
perimentally (Engelbrecht et al., 2007) and clinically (Mao et al., 2017;
Perez et al., 2010) validated in recent times, claims made for many
other plant extracts have not been scientifically investigated.
The use of plants for the management of cancer dates to several
centuries ago as reported in the ancient traditional folklore in Africa,
Asia and Europe. Numerous plant extracts and herb decoctions are
believed to possess the ability to prevent carcinogenesis, reduce tumor
sizes, or relieve cancer-related symptoms (Greenwell and Rahman,
2015; Sawadogo et al., 2012). While it may be a tedious task to es-
tablish the scientific validity of these claims for all suggested plant
products, the evidence presented by the sheer number of patients that
continue to patronise these traditional medicines (TM) –as either a
monotherapy, or as supplementary therapy to conventional drugs –
cannot be ignored (Paller et al., 2016). Furthermore, the number of
potential anti-cancer therapeutics isolated from plants and currently in
different stages of clinical trials keeps increasing (Newman and Cragg,

⁎
Corresponding author.
E-mail address: csmith@sun.ac.za (C. Smith).

https://doi.org/10.1016/j.jep.2018.09.037
Received 2 May 2018; Received in revised form 31 August 2018; Accepted 28 September 2018
Available online 01 October 2018
0378-8741/ © 2018 Elsevier B.V. All rights reserved.
A.B. Oyenihi, C. Smith
Fig. 1. The basic classification of polyphenols and their most commonly known plant sources. Plants are huge reservoirs for diverse classes of natural polyphenols
that can be harnessed for medical purposes.
2016; Nobili et al., 2009). This suggests that natural products may in-
deed become the panacea against this chronic disease – either as pre-
ventative medicine strategy, or at least to serve as templates for the
design of novel synthetic drugs. Most published studies on medicinal
plants with anti-cancer properties reported in the literature lack in-
depth investigation into specific active components to which these ef-
fects may be attributed. Thus, it is vital to continue efforts to more
narrowly elucidate and identify the specific plant components re-
sponsible for the anti-cancer attributes, as well as the optimal propor-
tions of these constituents in cases where mixtures of several plant
components are more effective than single isolates. This gap in the
scientific knowledge base has been a major limitation to the responsible
use of traditional medicine outside of the original, anecdotal scenario.
However, this deficit may be better addressed in future, given the more
recent attempts by regulatory agencies to standardize plant medicines
in terms of constituent levels and proportions – for example by de-
manding inclusion of phytochemical fingerprints in plant pharmaco-
poeias – to improve efficacy and patient safety (Ajazuddin and Saraf,
2012; Sahoo et al., 2010; Vlietinck et al., 2009). The key to under-
standing safety and efficacy of potential medicinal plants is an in-depth
knowledge of the phytochemicals present therein, which can only be
gained through comprehensive scientific characterisation and experi-
mentation.
In addition, some specific herbal products have been reported to
alter the metabolism and transport of anti-cancer agents (He et al.,
2010), while recent studies have reported the possible pharmacokinetic
(Cheng et al., 2018) and pharmacodynamic (Awortwe et al., 2018)
implications of adverse herb-drug interactions in patients. Given the
potential of plant extracts as complementary medicine in patients al-
ready prescribed pharmaceutical anti-cancer treatment, these reports
highlight the requirement for continued drug interaction studies to
ensure both consumer safety and maintained therapeutic efficacy.
Due to the seemingly unfavourable risk: benefit ratio of many cur-
rent anti-cancer pharmaceuticals, or perhaps as a result of the rigorous
guidelines put in place for plant-derived products, research into several
pure medicinal phytochemicals, such as vincristine, vinblastine, pacli-
taxel, genistein, lycopene, resveratrol etc. isolated from plant extracts,
have progressed to clinical trials with some already approved by the US
Food and Drug Administration (FDA) as anti-cancer drugs (Paller et al.,
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Journal of Ethnopharmacology 229 (2019) 54–72
2016). This further confirms that many anecdotal claims for anti-cancer
efficacy may be strong enough – and plant extracts potent enough – to
withstand rigorous scientific testing.
In our review of the relevant literature, in terms of anti-cancer
medicines, plant polyphenols seem to enjoy high prominence. The an-
tioxidant capacity of these polyphenols have been firmly established in
the literature, from in vivo supplementation studies in both rodents
(e.g. (Kruger and Smith, 2012; Myburgh et al., 2012)) and humans (e.g.
(McAnulty et al., 2013; Petersen et al., 2018) which clearly showed
decreased presence of oxidative damage, increased antioxidant capacity
(ferric-reducing ability of plasma (FRAP), Trolox equivalent antioxidant
capacity (TEAC), oxygen radical absorptive capacity (ORAC), etc.) in
both blood and tissue compartments after supplementation. Given this
undeniable role of polyphenols as a preventative medicine in many
other chronic conditions, such as ageing, cardiovascular disease and
diabetes (Petersen and Smith, 2016; Smith, 2018), the aim of this re-
view was to elucidate the relative importance of polyphenols in the
context of cancer. To this end, we reviewed the literature on popularly
researched anti-cancer medicinal plants in an attempt to assess the re-
lative importance of polyphenols relative to other plant actives, in
terms of anti-cancer mechanisms reported. As a starting point and to
explain the rationale for our interest in polyphenols more comprehen-
sively, a brief overview of mechanisms by which polyphenols may exert
their cancer-related effects is first presented. These mechanisms are
then compared to other commonly researched “non-polyphenolic”
plant products to sketch a holistic picture of the potential of plant
products and constituents in the context of cancer treatment. Finally,
the complexities and limitations, as well as the way forward, in terms of
natural product drug discovery, are presented.
2. Demonstrated cancer-related effects of polyphenols
Polyphenols represent one of the largest categories of plant com-
ponents, with several thousand individual polyphenol types adding
complexity to a comprehensive characterisation of any particular plant.
As comprehensively reviewed elsewhere (Tsao, 2010), typical poly-
phenols are phenol-containing compounds with carbon skeleton back-
bones ranging from C1-C6 to C3-C6 and C6-C3-C6 – but while some
contain the N-functional constituent, the chemical structures of other
A.B. Oyenihi, C. Smith
Fig. 2. Stages of cancer progression and cellular mechanisms for chemoprevention by polyphenols. Different types of polyphenols act in multiple ways to prevent
and/or slow down cancer progression.
atypical polyphenols are too complex to group together or categorise.
To facilitate our discussion, the most important, basic polyphenol
classes are illustrated in Fig. 1.
Chemoprevention strategies in cancer can be summarised to act via
4 major mechanisms: firstly, by modulating inherited traits or changes
in gene expression brought about by exposure to carcinogens and which
may activate the process of carcinogenesis, secondly by countering the
effects of exacerbating factors (such as stress) that promote cancer cell
development, thirdly by opposing cancer cell survival through mod-
ulation of cellular mechanisms and fourthly, by limiting the ability of
cancers to metastasise. In Fig. 2, we present these mechanisms and
indicate how the effects brought about by polyphenols are often mul-
tifaceted, with the most consistently reported mechanisms related to
stimulation of apoptosis (Curti et al., 2017; Engelbrecht et al., 2007)
and autophagy (Gali-Muhtasib et al., 2015), regulation of cellular sig-
naling cascades (Abdal Dayem et al., 2016; Lewandowska, H. et al.,
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Journal of Ethnopharmacology 229 (2019) 54–72
2016), epigenetic modulation (DNA methylation or histone post-
translational modifications) (Li, W. et al., 2016; Wu, J.C. et al., 2016),
inhibition of cell proliferation, angiogenesis and metastasis (Di Leo
et al., 2017; Morbidelli, 2016; Weng and Yen, 2012). In addition to the
mechanisms summarised in Fig. 2, polyphenols are also known to ex-
ploit their inherent antioxidant and anti-inflammatory properties to
halt carcinogenesis (Amani et al., 2017; Omidian et al., 2017), thereby
preventing or delaying progression and clinical manifestation of cancer.
However, as many reviews on the benefits of antioxidant and anti-in-
flammatory supplements in the context of chronic disease are available
(e.g. (Petersen and Smith, 2016; Smith, 2018; Xu et al., 2018; Yang
et al., 2018)), the potential of polyphenols as preventative medicine/
supplement was not included as topic in this review.
A major medicinal advantage of polyphenols is their demonstrated
ability to act on multiple molecular and cellular targets (as recently
exemplified by Kruger et al., 2014 and Smith, 2018). Thus, they employ
A.B. Oyenihi, C. Smith
different mechanisms that are of utmost relevance in combating carci-
nogenesis and preventing cancer resistance. However, the anti-cancer
value of most polyphenols is greatly limited by their low bioavailability
in in vivo situations due to the extensive metabolism (mostly glucur-
onidation, sulfation, and methylation) that occurs in tissues and by the
gut microbiota (Asensi et al., 2011; Estrela et al., 2017). These meta-
bolic changes ensure that the concentration of potent polyphenols that
finally get to the desired cancer site(s) may be beyond the optimal
therapeutic dose required for efficacy and safety – with the effective
dose threshold varying from one polyphenol to another (Estrela et al.,
2017). Given this complexity, the relative absence of in vivo assess-
ments of efficacy is a huge gap in the scientific literature which should
be addressed with urgency. Currently, although plant medicines or
polyphenols specifically are comprehensively assessed for effects using
pharmacological or in vitro models, but comprehensive in vivo studies
are relatively lacking. It thus remains to be tested (in the majority of
cases) whether these effects have sufficient clinical significance in a
physiologically relevant environment, where bioavailability limitations
come into play. Once such information becomes available, further re-
search efforts can continue to enhance the chemo-preventive effects of
polyphenols by increasing their bioavailability, properly designing
dose-response studies and developing novel target/site delivery sys-
tems, as these approaches – e.g. covalent modifications (Lewandowska,
U. et al., 2016), nano-formulations (Bhise et al., 2017; Bonferoni et al.,
2017) mitochondria-targeting (Gorlach et al., 2015) or micro-RNA-
targeting (Pandima Devi et al., 2017) – have been shown to increase
their anti-cancer potential. Combinations of different types of poly-
phenols or polyphenols in combination with other phytochemicals/
nutrients may also confer superior efficacy against cancer and become a
useful strategy with which to combat cancer resistance (Niedzwiecki
et al., 2016).
It is therefore pertinent to ascertain whether the polyphenol com-
ponent of plant extracts is one of the most important constituents re-
sponsible for their anti-cancer activities. If this hypothesis is true, re-
search efforts should be focused mainly on optimizing the medicinal
qualities of this key class of phytochemicals by determining effective
dose, bioavailability, efficacy and safety indices as it relates specifically
to chemoprevention. It will also help in substantiating anecdotal claims
of some plant extracts against cancer by simply assessing their poly-
phenol content/activities, which would aid in the screening of potential
medicinal plants, saving precious research time and resources. At the
moment, much of the available literature is not complete in enough in
terms of quantitative product characterisation to directly enable testing
of this hypothesis. However, a comparative integration of available data
on anti-cancer mechanisms commonly reported for plant products may
shed some light on this.
Interestingly, about half of the anti-cancer drugs currently em-
ployed in conventional medicine practices indeed contains phyto-
chemicals or synthetic derivatives of plant constituents (Moraes et al.,
2017). In terms of registered drugs, although only two (etoposide and
teniposide – which are semi-synthetic imitations of epipodophyllotoxin,
an isomer of podophyllotoxin isolated from the roots of the Podophyllum
species) are described primarily as polyphenols (Cragg and Newman,
2005; Lee and Xiao, 2012), many other noteworthy polyphenols de-
rived from plants are in different stages of drug development against
cancer. These include curcumin, epigallocatechin gallate, apigenin,
rosmarinic acid, resveratrol, gingerol, genistein, and quercetin
(Niedzwiecki et al., 2016; Singh et al., 2016). Etoposide and teniposide
are both DNA topoisomerase II inhibitors that have been extensively
indicated for a variety of cancer types, but the uses of these polyphenol
imitations are associated with undesirable outcomes such as myelosup-
pression, leukopenia, thrombocytopenia and hypersensitivity reactions.
Although this is a source of concern, the safety profiles for these drugs
are still more tolerable than those of other topoisomerase inhibitors
such as anthracyclines, anthraquinones or rebeccamycin analogues
(Hande, 1998; Hartmann and Lipp, 2006). Furthermore, their side-
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Journal of Ethnopharmacology 229 (2019) 54–72
effects may potentially be ascribed to their synthetic nature: a combi-
nation therapy approach – e.g. paired with a photodynamic therapy
(Luo et al., 2017), natural polyphenols like resveratrol, or fisetin
(Ferreira de Oliveira et al., 2018) – have shown potential to reduce the
side-effects of etoposide while at the same time enhancing the ther-
apeutic effect achieved.
In contrast, isolated reports have indicated that antioxidant (in-
cluding polyphenol) supplementation may increase the survival of
cancerous cells to promote cancer resistance to other chemotherapeutic
drugs. This interpretation probably arose from studies indicating that
the common oncogenes ras and myc upregulated the antioxidant tran-
scription factor Nrf2 to evade death and contributed to the cancer-cell
resistance to drugs such as DNA topoisomerase II inhibitors (Chen et al.,
2017; DeNicola et al., 2011; Menegon et al., 2016). The exogenous
administration of antioxidants can then be seen to firstly potentiate the
Nrf2-dependent processes in cancerous cells and secondly, to inhibit the
activities of co-administered chemotherapeutic agents that function via
the generation of reactive oxygen species (ROS).
Taken together, these results indicate that within a plant extract
“cocktail”, different constituents may have opposing effects in the
context of cancer. This highlights the importance of elucidation of
mechanisms of action and interactions between different plant actives
and to include in vivo trials in order to accurately assess the net effect of
these constituents when in combination. The inconclusiveness of pre-
vious clinical trials which mostly relied on therapeutic endpoints in
relatively small patient cohorts should not be a deterrent to future
studies. Rather, novel ways to extrapolate the overwhelming beneficial
evidence seen in pre-clinical studies to humans must be developed. For
example, pre-clinical studies should be carefully designed by choosing
appropriate cellular models to determine specific early molecular tar-
gets and the optimum dose before embarking on clinical trials (Russo
et al., 2017). Also, to more sensitively detect positive chemo-preventive
effects of natural products in well-designed clinical trials, more ad-
vanced data analysis methods may be required – e.g. focusing on in-
dividual rather than group average responses to treatment, as recently
demonstrated (Smith, 2018).
3. Medicinal plant constituents in extracts with anti-cancer effects
Turning attention now to specific plant compounds with potential
anti-cancer effect, a plethora of medicinal plant extracts containing
numerous classes of phytochemicals (such as polyphenols, alkaloids,
saponins, terpenoids, brassinosteroids etc.) have been identified to
possess potent anti-cancer properties (Aung et al., 2017; Greenwell and
Rahman, 2015; Orlikova and Diederich, 2012). Unfortunately, the re-
ported anti-cancer properties were not attributed to specific phyto-
chemicals in the plant extracts for most of the earlier studies. Experi-
mental studies where comprehensive phytochemical characterisation
had been performed and mechanisms of actions suggested, only became
the norm fairly recently when it became a prerequisite for publishing in
reputable journals. In these experiments, the phytochemical class of
polyphenols seem to be predominantly present in most of the plant
extracts widely used in cancer management (Cai et al., 2004; Dai and
Mumper, 2010; Niedzwiecki et al., 2016; Wu, J.C. et al., 2016; Zhou
et al., 2016). Hence, the importance of polyphenol-rich anti-cancer
medicinal plants cannot be over-emphasized. Some of these plants in-
clude Vitis vinifera, Ocimum sanctum, Oroxylum indicum, Momordica
charantia, Zingiber officinalis, Ceratonia siliqua, Vernonia amygdalina,
Camellia sinensis, Azadirachta indica, Pimenta dioica, Pygeum africanum,
Glycine max, Aronia melanocarpa, Scutellaria barbata, Olea europaea,
Punica granatum and Vaccinium macrocarpon. The parts of plants used
for the preparation of extracts, the type of polyphenols identified within
extracts, as well as the types of cancer in which efficacy testing has
commonly been performed in both in vitro and in vivo investigations
are summarised in Table 1. For clarity of presentation, more specific
details on dosage and treatment duration are presented separately in
 Table 1
Some widely studied polyphenol-containing plant extracts used in cancer management.
Plant (common name) Traditional Plant part Common polyphenols Types of cancer Mechanisms of action References
uses (s) used for present tested
extract Cell Epigenetic Antioxidant Anti- Inhibition of Apoptosis, Inhibition of
cycle modulation inflammatory or pro-survival necrosis or cell migration
A.B. Oyenihi, C. Smith

arrest immune system cell signaling autophagy and/or

modulation angiogenesis

Vitis vinifera L. (Grapes) Food and
wine, more recently as anti-
oxidant supplement.
Ocimum sanctum L. (Holy basil)
Cancer.
Oroxylum indicum (L.) Kurz
(midnight horror, oroxylum,
Indian trumpet flower,
broken bones, Indian caper,
or tree of Damocles) Tonic
with analgesic and gastro-
protective properties.
Momordica charantia L. (Bitter
Fruit, seed, Proanthocyanidins, Breast, colon, ✓ ✓ ✓ ✓ ✓ ✓ ✓ (Dinicola et al., 2010;
stem, skin, catechins, gallic acid, renal, thyroid, Engelbrecht et al., 2007;
leaf resveratrol, quercetin, liver, cervical Gollucke et al., 2013;
rutin, kaempferol Sahpazidou et al., 2014;
Stagos et al., 2014; Zhou and
Raffoul, 2012)
Leaf Rosmarinic acid, luteolin, Oral, prostate, ✓ ✓ ✓ ✓ (Bhattacharyya and
orientin, eugenol, vicenin lung, breast, Bishayee, 2013;
gastric, skin, Dhandayuthapani et al.,
pancreatic 2015; Kwak et al., 2014;
Shimizu et al., 2013;
Shivpuje et al., 2015)
Fruit, stem Bicalein, oroxins A & B, Leukaemia, ✓ ✓ (Dinda et al., 2015; He, J.
bark, leaf chrysin, scutellarin lymphoma, et al., 2016; Lalou et al.,
breast 2013; Roy et al., 2007; Yang
et al., 2015)
Fruit, seed, Catechins, coumaric acid, Skin, breast, ✓ ✓ ✓ (Dandawate et al., 2016;

58
melon) Diabetes-related
ailments
Zingiber officinalis Roscoe (Ginger)
Mostly for pain management
Ceratonia siliqua L. (Carob tree)
Chocolate substitute
Vernonia amygdalina Delile (Bitter
leaf) Headache, fever,
malaria, diarrhoea,
dysentery, hepatitis,
coughing, as laxative or
fertility inducer
Camellia sinensis (L.) Kuntze (Tea
plant) Stimulant properties
Curcuma longa L. (Turmeric)
Hepatoprotective, anti-
inflammatory,
anticarcinogenic,
antimicrobial
Azadirachta indica A. Juss. (neem,
nimtree or Indian lilac)
Antihelmintic, Antiseptic,
anti-diabetic, sedative,
contraceptive,
leaf ferulic acid, caffeic acid prostate, colon, Raina et al., 2016; Yung
lung, stomach, et al., 2016)
cervical, ovary
Rhizome, Gingerol, shogaol Breast, skin, GIT, ✓ ✓ (Bernard et al., 2017;
leaf, root colon Choudhury et al., 2010;
Shukla and Singh, 2007)
Leaf Gallic acid, coumaric Colon ✓ ✓ ✓ (Corsi et al., 2002; Ghanemi
acid, quercetin, catechins et al., 2017; Klenow et al.,
2009)
Leaf, root Luteolin Breast ✓ ✓ ✓ (Howard et al., 2016; Wong
et al., 2013; Yedjou et al.,
2013)
Leaf Catechins, rutin, Prostate, colon, ✓ ✓ ✓ ✓ ✓ (Hajiaghaalipour et al.,
quercetin gastric, breast 2015; Luo et al., 2014; Sur
and Panda, 2017; Yang et al.,
2013)
Rhizome, Curcumin Liver, colon, ✓ ✓ ✓ ✓ (Abdel-Lateef et al., 2016; Li
root skin, pancreas, et al., 2014; Schaffer et al.,
breast 2015; Yue et al., 2016)
Leaf, Catechins, quercetin, Breast, prostate, ✓ ✓ ✓ ✓ ✓ ✓ (He, Z. et al., 2016; Liu et al.,
flower, seed nimbaflavone, skin, GIT, colon, 2015; Patel et al., 2016; Wu
nimbandiol, liver et al., 2014)
(continued on next page)
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 1 (continued)

Plant (common name) Traditional Plant part Common polyphenols Types of cancer Mechanisms of action References
uses (s) used for present tested
extract Cell Epigenetic Antioxidant Anti- Inhibition of Apoptosis, Inhibition of
cycle modulation inflammatory or pro-survival necrosis or cell migration
A.B. Oyenihi, C. Smith

arrest immune system cell signaling autophagy and/or

modulation angiogenesis

Pimenta dioica (L.) Merr. (Allspice) Berry Ericifolin Breast, prostate ✓ ✓ ✓ (Shamaladevi et al., 2013;
Tooth and gum health (Allspice) Zhang et al., 2015a)
Prunus africana (Hook.f.) Kalkman Root-bark Atraric Acid, Ferulic acid Prostate, head ✓ ✓ ✓ (Komakech et al., 2017;
(African cherry) Benign and neck Schmidt et al., 2013;
hyperplasia Shenouda et al., 2007)
Glycine max (L.) Merr. (Soybeans) Seed Genistein, daidzein, Breast, prostate, ✓ ✓ ✓ ✓ ✓ ✓ (Amaral et al., 2017; Dong
Protein replacement Glycetein ovarian, colon, et al., 2013; Mahmoud et al.,
liver, leukaemia 2014; Russo et al., 2016;
Vilela et al., 2014)
Aronia melanocarpa (Michx.) Elliott Berry Anthocyanins, Brain, pancreas, ✓ ✓ ✓ ✓ (Abdullah Thani et al., 2012;
(Chokeberry) Anxiety, hydroxycinnamic acids, leukaemia, Bermudez-Soto et al., 2007;
diarrhoea, colds, catechins, quercetin breast, colon Jurikova et al., 2017; Sharif
tuberculosis et al., 2012)
Scutellaria barbata D.Don (Barbed Leaf, Scutellarin, Apigenin, Lung, breast, ✓ ✓ ✓ (Gao et al., 2017; Kan et al.,
skullcap – in the mint family) rhizome luteolin prostate, colon, 2017; Lin, J. et al., 2014;
Anti-tumorigenic ovary, liver, GIT Shim et al., 2016; Yang et al.,
2017; Zhang et al., 2017)
Olea europaea L. (Olive) General Leaf, fruit, Oleuropein, 3- Pancreas, breast, ✓ ✓ ✓ ✓ ✓ (Boss et al., 2016;
cleanser and moisturiser; oil hydroxytyrosol, luteonin, leukaemia, Makowska-Was et al., 2017;
fruit and oil consumed as apigenin prostate, colon, Samet et al., 2014; Tezcan
food glioblastoma et al., 2017; Zeriouh et al.,

59
2017)
Punica granatum L. (Pomegranate) Fruit, seed, Anthocyanins Prostate, skin, ✓ ✓ ✓ ✓ (Deng et al., 2017;
Heart disease, hypertension, peel, leaf breast, lung, Khwairakpam et al., 2018;
inflammation, cancer colon, liver, Kiraz et al., 2016; Li, Y.
leukaemia et al., 2016; Panth et al.,
2017; Sharma et al., 2017;
Song et al., 2016)
Vaccinium macrocarpon Aiton Fruit Catechins Esophageal, ✓ ✓ (Deziel et al., 2012; Kresty
(Cranberry) Urinary tract prostate, GIT, et al., 2015; MacLean et al.,
ailments urinary bladder 2011)
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 2
Summary of commonly used in vitro models and dosage regimen of the widely studied polyphenol-rich plant extracts in cancer management.
Plant Extract Plant part Method of anti-cancer assessment/cancer Dosage range Major anti-cancer outcome measures References
used cell line(s) tested

Vitis vinifera L. Hydrochloric acid/ Seed MTT assay/Colon CaCo2 cells 10–100 µg/ml for 24 h Decreased mitochondrial viability; inactivated the PI-3K/ (Engelbrecht et al., 2007)
A.B. Oyenihi, C. Smith

ethanol/water PKB pathway; increased cleaved caspase-3 and PARP

expressions
Hydrochloric acid/ Seed Trypan blue exclusion method / Head and 20, 40 µg/ml for 12–72 h Decreased cell viability; increased intracellular ROS; (Shrotriya et al., 2012)
ethanol/water Neck squamous Detroit 562 and FaDu cells activated DNA damage & cell cycle checkpoint cascades and
caspase-8, -9, -3; and reduce DNA repair molecules
Methanol /hydrochloric Stem SRB assay / Colon (HT29), breast (MCF-7, 12.5–400 µg/ml for 72 h Decreased cell viability (Sahpazidou et al., 2014)
acid/water MDA-MB-23), kidney (786-0, Caki-1) and
thyroid (K1) cells
Ocimum sanctum L. Ethanol Leaf Trypan blue exclusion method / Prostate 50–200 µg/ml for 24 or Decreased cell viability; depolarized the mitochondrial (Dhandayuthapani et al.,
LNCaP cells 48 h membrane potential; increased PARP cleavage and caspase- 2015)
3, -9 activities; and decreased Bcl2 expression
Ethanol Leaf MTT assay / Lung NCI-H460 cells 6–200 µg/ml for 24 h Decreased mitochondrial viability; inhibited cell adhesion (Kwak et al., 2014)
and invasion; decreased OPN & CD44 expressions; and
suppressed PI-3K/Akt, COX-2, uPA, uPAR, MMP-9, VEGF &
EGFR expressions
Oroxylum indicum (L.) Methanol Fruit Trypan blue exclusion method / Leukemia 10–50 µmol/l for 24 h Decreased cell viability; blocked cells at S or G2M phases; (Roy et al., 2007)
Kurz HL-60 cells and increased DNA fragmentation
Petroleum ether/ethyl Stem bark MTT and XTT assays / Cervical HeLa, and 10 µg/ml for 24 h Decreased mitochondrial viability; induced NF-κB-dependent (Siriwatanametanon et al.,
acetate/methanol leukemia CCRF-CEM cells antioxidant and anti-inflammatory activities 2010)
Petroleum ether/ Stem bark XTT assay / Breast MDA-MB-231 and MCF-7 25–200 µg/ml for 24 h Decreased mitochondrial viability; increased DNA (Kumar et al., 2012)
chloroform cells fragmentation and reduced cell migration distance
Petroleum ether/ Leaf Methylene blue assay/Cervical HeLa cells 0.39–99 µg/ml for 72 h Decreased cell viability; induced p53 and Bax levels; and (Zazali et al., 2013)
methanol blocked cells at G1S phase

60
Momordica charantia L. Water Fruit XTT and focus formation assays / Ovarian 0.25–0.1% v/v for 5 days Decreased mitochondrial viability and cell colonies; induced (Yung et al., 2016)
A2780cp, A2780s, C13*, OV2008, SKOV3, cell cycle arrest; increased cleavage of PARP and caspase -3;
OVCA433 and ES2 cells activated SAPK/JNK, c-Jun, p38, MAPKAPK-2, and HSP27;
and decreased cell migration
Ethanol Leaf WST-1 assay/Prostate PLS10 cells 10–200 µg/ml for 24 or Decreased mitochondrial viability; inhibited cell migration (Pitchakarn et al., 2010)
48 h and invasion; reduced MMP-2 & -9 and uPA secretion;
inhibited collagenase type IV activity
Methanol Whole fruit, Hexosaminidase and clonogenicity assays / 10–400 µg/ml for 48 h or Decreased mitochondrial viability; blocked cells at S or G2M (Kwatra et al., 2013)
skin Colon HT-29 and SW480 cells 7 days phases; induced LC3B cleavage; decreased Bcl-2; increased
Beclin-1, ATG 7,12 levels; reduced cellular ATP level and
activated AMPK; and inhibited DCLK1 and LGR5 expressions
Zingiber officinalis Methanol Leaf MTT assay / Colon HCT116, SW480 and 50–200 µg/ml for 24 or Decreased mitochondrial viability; stimulated activating (Park et al., 2014)
Roscoe LoVo cells 48 h transcription factor-3 promoter activity; and activated ERK1/
2
Water Rhizome Trypan blue exclusion method and MTT 25–500 µg/ml for 24 h Decreased cell & mitochondrial viability; impaired (Choudhury et al., 2010)
assay / Lung A549 and cervical HeLa cells mitochondrial membrane potential; inhibited microtubule
structure & functions; increased p53 & Bax expressions; and
decreased Bcl2 & pro-caspase-3 expressions
Ceratonia siliqua L. Methanol/acetone/ Leaf Trypan blue exclusion method / Colon 5–100 µg/ml for 24 h Decreased cell viability; increased apoptotic cells; activated (Ghanemi et al., 2017)
water HCT116 and CT-26 cells MAPK, p53, cleavage of caspase-9 and PARP; increased
caspases-3, -7 activities; elevated p27, cyclins A & E
expressions; and reduced CDK2 level
Ethanol Pod MTT assay / Cervical HeLa and breast MCF-7 0.5–1.2 mg/ml for 48 h Decreased mitochondrial viability (Roseiro et al., 2013)
cells
Water Leaf, pod BrdU assay / Liver T1 cells 0.1–1 mg/ml for 24 h Decreased cell viability; induced DNA fragmentation and (Corsi et al., 2002)
increased caspase-3 activity
(continued on next page)
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 2 (continued)

Plant Extract Plant part Method of anti-cancer assessment/cancer Dosage range Major anti-cancer outcome measures References
used cell line(s) tested

Vernonia amygdalina Water Leaf Trypan blue exclusion method / Breast 100 µg/ml for 18 h Decreased cell viability; inhibited DNA synthesis and (Howard et al., 2016)
A.B. Oyenihi, C. Smith

Delile MDA-MB-231, HCC-70, SK-BR-3, HCC 1806, induced DNA damage; increased p-glycoprotein ATPase
MDA-MB-468 and MCF-7 cells activity; increased cleaved caspase-3 & Bax/Bcl2 ratio; and
activated ERK1/2
Ethanol Leaf MTT assay / Breast MCF-7 and MDA-MB-231 50–200 µg/ml for Decreased mitochondrial viability; elevated p53 & p21 levels (Wong et al., 2013)
cells 24–72 h and reduced cyclin D1& E levels; increased cleaved PARP
and reduced procaspase-7, -8, -9 expressions; increased Bax
& Bak levels and decreased Bcl2 & Bclxl levels; inhibited ER-
α expression and Akt phosphorylation
Camellia sinensis (L.) Water Leaf WST-1 assay / Lymphoma U937, KMH2, 0.1–1 mg/ml for 24 h Decreased mitochondrial viability; caused ROS-independent (Philion et al., 2017)
Kuntze L540 and HDMYZ cells mitochondrial depolarization and decreased oxygen
consumption
Water Leaf MTT assay / Colon HT29 cells 10–100 µg/ml for 48 h Decreased mitochondrial viability; increased caspase-3, -8 & (Hajiaghaalipour et al.,
-9 activities 2015)
Water Leaf MTT assay / Breast 4T1 cells 0.2–1 mg/ml for 24–72 h Decreased mitochondrial viability; elevated Bax/Bcl2 (Luo et al., 2014)
expression ratio and activated caspase-3 & -8; and inhibited
cell migration and invasion
Curcuma longa L. Methanol Rhizome MTT assay / Lung A549, colon HT29 and 1–10 µg/ml for 72 h Decreased mitochondrial viability (Kukula-Koch et al., 2018)
glioblastoma T98G cells
Methanol Rhizome Neutral red assay / Liver HepG2 cells 15–2000 µg/ml for 72 h Decreased cell viability; and increased apoptotic cells (Abdel-Lateef et al., 2016)
Azadirachta indica A. Supercritical CO2 Leaf MTT assay / Colon HCT116 and HT29 cells 1–150 µg/ml for 48 or Decreased mitochondrial viability; increased Bax/Bcl-2 ratio (Patel et al., 2018)
Juss. 72 h and reduced Cyclin D1 expression; reduced STAT3 and NF-κB
expressions; inhibited cell migration; and decreased COX1,
IL-6 & TNF-α, and MMP-2 & -9 expressions
Pimenta dioica (L.) Merr. Water Berries MTT and clonogenicity assays, Trypan blue 25–200 µg/ml for 72 h or Decreased mitochondrial & cell viability; increased LC3B and (Zhang et al., 2015a)

61
exclusion method / MCF7, MB231, T47D, 10–12 days autolysosome levels; and downregulated Akt-mTOR
Breast SKBR3 and BT474 cells signaling
Water Berries MTT assay / Prostate LNCaP cells 50– 200 µg/ml for 48 h Decreased mitochondrial viability; inhibited histone (Lee et al., 2007)
acetyltransferase activity and reduced androgen receptor
genes expressions (PSA and TSC22)
Prunus africana Ethanol Stem-bark Thymidine incorporation assay / Prostate 2.5–10 µl/ml for 72 h Decreased cell proliferation rate; blocked cells in the S phase; (Shenouda et al., 2007)
(Hook.f.) Kalkman LNCaP cells increased apoptotic cells; reduced ER-α & PKC-α expressions
Glycine max (L.) Merr. Isopropanol and fungi- Seed MTT and thymidine incorporation assays / 0.11– 2.3 µmol/l for Decreased mitochondrial viability; blocked cells in the G2/M (Amaral et al., 2017)
bio-transformed Breast MCF-7aro cells 24–72 h phase; and inhibited DNA synthesis; and inhibited aromatase
activity
Fungi-bio-transformed Seed MTT assay / Melanoma A375 and 451Lu 0.4–2.2 mg/ml for 24 h Decreased mitochondrial viability; increased caspase-3 (Vilela et al., 2014)
cells activity and PARP cleavage; induced caspase-7, -8 and
TNFR2, TRAIL, DR-4 & NF-κB expressions
Aronia melanocarpa Water Berry MTS assay / Leukemia Jurkat cells 0.1–0.5% v/v for 24 h Decreased mitochondrial viability; blocked cells in the G2/M (Sharif et al., 2012)
(Michx.) Elliott phase; induced p73-dependent activation of caspase-3, and
inhibited cyclin B1 & UHRF1 expressions; increased
intracellular ROS; disrupted mitochondrial membrane and
increased cytochrome c level
Water Berry MTT assay / Glioblastoma U373 cells 100–600 µg/ml for 72 h Decreased mitochondrial viability; reduced MMP-2, -14, -16 (Abdullah Thani et al., 2012)
& -17 expressions
Water Berry Trypan blue exclusion method / Colon CaCo- 50– 800 µmol/l for 2 h Decreased cell viability; blocked cells in the G2/M phase; (Bermudez-Soto et al., 2007)
2 cells daily for 4 days upregulated CEACAM1 expression
Scutellaria barbata D. Ethanol Leaf, rhizome MTT assay / Ovarian A2780 cells 50–600 µg/ml for 24 and Decreased mitochondrial viability; increased apoptotic cells, (Zhang et al., 2017)
Don 48 h caspase-3, & -9 expressions and decreased Bcl-2; inhibited
cell migration and MMP-2, & -9 expressions
Ethanol Rhizome MTT assay / Gastric MKN-45 cells 40–200 µg/ml for 24 and Decreased mitochondrial viability; blocked cells at sub-G1 (Shim et al., 2016)
72 h phase; increased mitochondrial membrane depolarization
and caspase-3, & -9 activities; inhibited MAPK & Akt; and
elevated intracellular ROS level
(continued on next page)
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 2 (continued)

Plant Extract Plant part Method of anti-cancer assessment/cancer Dosage range Major anti-cancer outcome measures References
used cell line(s) tested

Olea europaea L. Ethanol Leaf Boyden chamber invasion assay / 2 mg/ml for 24 h Reduced cell migration (Tezcan et al., 2017)
A.B. Oyenihi, C. Smith

Glioblastoma T98G cells

Methanol/acetone/ Leaf MTT assay / Colon HCT8 and HCT116 cells 5–70 µg/ml for 24 h Decreased mitochondrial viability; induced PARP and (Zeriouh et al., 2017)
water caspase-9 cleavage and increased caspase-3, -7 expressions;
reduced mitochondrial membrane potential; elevated ROS-
dependent endoplasm reticulum stress; and increased
intracellular Ca2+ levels
Ethanol Leaf MTT assay / Leukemia K562 cells 50–150 µg/ml for 24, 48, Decreased mitochondrial viability; blocked cells in the G0/G1 (Samet et al., 2014)
and 72 h and G2/M phases; induced monocyte/macrophage
differentiation; and upregulated IFI16, EGR1, NFYA, FOXP1,
CXCL2, CXCL3, and CXCL8 expressions
Punica granatum L. Ethanol Peel MTT and clonogenicity assays / Prostate 12.5–200 µg/ml for 24, Decreased mitochondrial viability & cell colonies; elevated (Deng et al., 2017)
DU145, PC3, and TRAMP-C1 cells 48, and 72 h or 7–10 apoptotic cells, Bax/Bcl-2 ratio and cleaved caspase-3
days expression; reduced mitochondrial membrane potential;
elevated intracellular ROS; inhibited cell migration,
decreased MMP-2, & -9 levels and increased TIMP-2
expression
Methanol Leaf, stem, MTT assay / Myeloma U266 cells 1–500 µg/ml for 48 and Decreased mitochondrial viability; increased apoptotic cells; (Kiraz et al., 2016)
flower and 72 h reduced mitochondrial membrane potential; and blocked
fruit cells at G2/M & S phases
Ethanol Fruit MTT assay / urinary bladder urothelial T24, 50 µg/ml for 24–72 h Decreased mitochondrial viability; increased Diablo, profilin (Wu, T.F. et al., 2016)
J82 and TSGH8301 cells 1, TPI1, NDUFAF1 and PSMF1/PI31 expressions; suppressed
the PTEN/Akt/mTOR pathway; and impaired cellular
aerobic glycolysis
Vaccinium macrocarpon Acetone/water Fruit WST-1 and BrdU assays / Esophageal JH- 10–100 µg/ml for 24 and Decreased mitochondrial viability; blocked cells at G2/M (Kresty et al., 2015)

62
Aiton ESOAd1, OE33 and OE19 cells 48 h phase; inhibited PI3K/Akt/mTOR signaling; induced Bax,
Bak1, deamidated Bcl-xl, cytochrome c, and PARP
expressions
Methanol/acetone/ Fruit Alamar Blue assay / Prostate DU145 cells 25 or 50 µg/ml for Decreased mitochondrial viability; reduced cells in G2M (Deziel et al., 2012)
water/formic acid 24–72 h phase; reduced CDK4, cyclin A, B, & E and increased p27
expressions
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 3
Summary of commonly used in vivo models and dosage regimen of the widely studied polyphenol-rich plant extracts in cancer management.
Plant Extract Plant part Animal model Dosage range Major anti-cancer outcome measures References
used
A.B. Oyenihi, C. Smith

Vitis vinifera L. Hydrochloric acid/ Seed Mouse tumor xenografts with Detroit 0.2% w/w ad libitum in the diet for 26 days Reduced tumor weight/volume; increased DNA damage (Shrotriya et al., 2012)
ethanol/water 562 and FaDu cancer cells and apoptotic cells
Wine Fruit Mouse tumor xenografts with C26 colon 100 mg/kg in drinking water daily for 25 Decreased tumor size; decreased Ki67, cyclin D1 & (Walter et al., 2010)
cancer cells days UHRF1 expressions; increased caspase-3 level; reduce
VEGF, MMP-2,9, & COX-2 expressions; and induced
p16INK4A, p53, and p73 expressions
Ocimum sanctum L. Ethanol Leaf Mouse xenografts with Lewis Lung 50–100 mg/kg by intraperitoneal injection Decreased tumor nodule formation; increased superoxide (Kim et al., 2010)
carcinoma cells once every 2 days for 18 days dismutase, catalase and glutathione peroxidase activities
Momordica charantia L. Water Fruit Mouse xenograft with ES2 ovarian 10% v/v by intraperitoneal injections once Reduced tumor weight (Yung et al., 2016)
cancer cells every 2 days for 12 days
Methanol Fruit Rat diethyl nitrosamine/carbon 40 mg/kg body weight daily for 30 days Decreased tumor incidence and size; reduced COX-2 and (Ali et al., 2018)
tetrachloride-induced hepatic cancer histone deacetylase activities; decreased VEGF and MMP-
2 & -9 levels; and elevated caspase-3 & -8 levels
Ethanol Leaf Mouse xenografts with prostate PLS10 or 1% w⁄w ad libitum in the diet daily for 3 Promoted mice survival rates; decreased tumor number, (Pitchakarn et al., 2010)
cancer cells weeks weights and metastatic area
Zingiber officinalis Ethanol Rhizome Mouse xenografts with 1–5 g/kg body weight daily for 30 days Reduced tumor growth; prolonged survival time (Plengsuriyakarn et al.,
Roscoe cholangiocarcinoma CL6 cancer cells 2012)
Ceratonia siliqua L. Methanol/acetone/ Leaf Mouse xenografts with CT-26 colon 1% infusion in drinking water ad libitum Reduced tumor growth (Ghanemi et al., 2017)
water cancer cells daily for 19 days
Vernonia amygdalina Water Leaf Mouse xenografts with HMLEH-RAS, 10, 20 mg/kg by subcutaneous pre- Reduced tumor volume (Howard et al., 2016)
Delile MDAMB-231 or MDA-MB-468 breast treatment for 10 days followed by daily
cancer cells treatment for 16 days or treatment daily for
16 days
Camellia sinensis (L.) Water Leaf Mouse xenografts with U-937 80 mg/kg in drinking water every 2 days for Reduced tumor volume; increased γ-H2AX (Philion et al., 2017)

63
Kuntze lymphoma cells 3 weeks phosphorylation and decreased PCNA expression
Water Leaf Mouse xenografts with 4T1 breast 600 mg/kg orally fed daily for 28 days Reduced tumor weight; decreased bone volume and (Luo et al., 2014)
cancer cells RANKL-induced osteoclasts
Curcuma longa L. Ethanol Rhizome Mouse xenografts with HT29 colon 400 mg/kg orally daily for 21 days Reduced tumor weight; and decreased CD31 and Factor (Yue et al., 2016)
cancer cells VIII expressions
Azadirachta indica A. Supercritical CO2 Leaf Mouse xenografts with HT29 and 200, 400 mg/kg in diet daily for 21 days Decreased tumor volume and reduced pro-inflammatory (Patel et al., 2018)
Juss. HCT116 colon cancer cells cytokine levels
Methanol Seed Mouse xenografts with H22 hepatoma 150–600 mg/kg by intragastric intubation Reduced tumor volume/weight; and increased survival (He, Z. et al., 2016)
cells daily for 25 days rate
Pimenta dioica (L.) Water Berries Mouse xenografts with MB231 breast 150 mg/kg by oral gavage daily for 10 Delayed tumor appearance, reduced tumor incidence and (Zhang et al., 2015a)
Merr. cancer cells weeks (2 weeks before and 8 weeks after growth; and increased LC3B expression
tumor induction)
Prunus africana Ethanol Stem-bark Mouse TRAMP model 128 mg/kg in the diet for 5 months Reduced tumor incidence (Shenouda et al., 2007)
(Hook.f.) Kalkman
+ +
Scutellaria barbata D. Ethanol Rhizome Mouse xenografts with H22 hepatoma 50–150 mg/kg by intragastric intubation Reduced tumor volume; downregulated CD4 , CD25 , (Kan et al., 2017)
Don cells daily for 30 days Foxp3+ Treg cells & Th17 cells; reduced IL-10, TGF-β, IL-
17A levels and elevated IL-2 & IFN-γ levels
Ethanol Leaf, Mouse xenografts with HT-29 colon 2 g/kg by intragastric intubation daily (6 Reduced tumor volume/weight; decreased cyclin D1 & (Lin, J. et al., 2014)
rhizome cancer cells days weekly) for 16 days CDK4 and increased p21; elevated apoptotic cells and
Bax/Bcl-2 ratio; and suppressed STAT3, ERK, and p38
signaling
Olea europaea L. Ethanol Leaf Chick embryo chorioallantoic 1–2 mg/ml for 10 days Inhibited tumor growth and decreased VEGFA expression (Tezcan et al., 2017)
membrane assay
Methanol/acetone/ Leaf Mouse xenografts with HCT116 colon 1% infusion in drinking water daily for 30 Reduced tumor surface area (Zeriouh et al., 2017)
water cancer cells days
Punica granatum L. Water Fruit Mouse dimethylbenz[α]anthracene and 10% v/v in drinking water ad libitum daily Delayed tumor onset and reduced tumor incidence; (George et al., 2011)
TPA-induced skin cancer for 2 and 28 weeks activated NF-κB; and decreased phospho-ERK1/2, JNK1
expressions
Vaccinium macrocarpon Acetone/water Fruit Mouse xenografts with OE19 250 µg/mouse by oral gavage 6 days a week Reduced tumor volume; inhibited PI3K/Akt/mTOR (Kresty et al., 2015)
Aiton esophageal cancer cells for 19 days signaling; and induced LC3B level
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 4
Some widely studied plant extracts where anti-cancer effects are mainly due to non-polyphenol phytochemicals.
Plant (common names) Plant part Major phytochemicals Types of cancer Mechanisms of action References
Traditional uses (s) used present tested
for extract Cell Epigenetic Antioxidant Anti- Inhibition of Apoptosis, Inhibition of cell
cycle modulation inflammatory or pro-survival necrosis or migration and/
A.B. Oyenihi, C. Smith

arrest immune system cell signaling autophagy or angiogenesis

modulation

Taxus brevifolia Nutt. (Pacific
yew) Induces
perspiration, treat
internal injuries and lung
diseases
Camptotheca acuminata Decne.
(Cancer tree) Cancer
Catharanthus roseus (L.) G.Don
(Periwinkle)
Gonorrhoea, diabetes,
menstrual regulator,
hypertension, cancer
Cephalotaxus harringtonia
(Knight ex J.Forbes)
K.Koch (Plum yew,
cowtail pine) Cancer
Hydrastis canadensis L.
(Goldenseal) Colds,
upper respiratory tract
Stem, Palcitaxel Ovarian, breast, ✓ (Wani and Horwitz, 2014;
bark lung cervical Wani et al., 1971)
Leaf, seed, Camptothecins Endometrial, ✓ (Lin, C.S. et al., 2014;
fruit leukaemia, ovarian, Zhang et al., 2007)
lung, colorectal
Fruit Vinblastine, vincristine Leukaemia, ✓ (Noble, 1990; Widowati
lymphoma, et al., 2013)
testicular, breast,
lung
Leaf, stem Harringtonine, Leukaemia ✓ ✓ (Pérard-Viret et al., 2017;
homoharringtonine, Takano et al., 1997;
isoharringtonine Wetzler and Segal, 2011)
Root, Berberine, hydrastine, Gastric, hepatic, ✓ ✓ ✓ ✓ (Goto et al., 2012;
rhizome palmatine, canadine lymphoma Karmakar et al., 2010;
Saha et al., 2013; Weber

64
infections, hay fever,
digestive disorders
Handroanthus impetiginosus
(Mart. ex DC.) Mattos
(Taheebo) Cancer,
inflammation, fungal
infections
Coix lachryma-jobi L. (Job's
tears) Inflammation
Peganum harmala L. (Wild rue)
Skin infection, pain, skin
cancer
Berberis vulgaris L. (Barberry)
Coughs, liver disease,
depression,
hyperlipidaemia,
bleeding, fever
Annona squamosa L. (Sugar
apple) Dysentery,
diarrhoea, colds, coughs,
hypertension
Trigonella foenum-graecum L.
(Fenugreek) Muscle pain,
cramps, hypertension,
liver disease, appetite
suppressor
Tree bark β-lapachone,
furanonaphthoquinone
Seed Kanglite, Coixspirolactams,
coixlactam, methyl
dioxindole-3-acetate,
Seed, root, Harmine, harmaline,
fruit vasicine, vasicinone
Fruit Berberine
Leaf, seed, 2, 15-cis-squamostatin-A,
seed oil bullatacin, fatty acids
Seed Trigonelline, diosgenin
Olomoucine, isothiocyanates
et al., 2003)
Breast, leukaemia, ✓ ✓ (Kung et al., 2014;
prostate, lung Lamberti et al., 2013;
Mukherjee et al., 2009;
Zhang et al., 2015b)
Lung, colon, uterine ✓ ✓ ✓ ✓ (Chang et al., 2018, 2003;
sarcoma Lee et al., 2008; Manosroi
et al., 2016; Son et al.,
2017)
Lung, colon, gastric, ✓ ✓ (Bournine et al., 2017;
breast Lamchouri et al., 2000; Li
et al., 2017)
Leukaemia, breast, ✓ ✓ ✓ (Ghafourian et al., 2017;
hepatic Ren et al., 2016; Saedi
et al., 2015)
Hepatic, colon, ✓ ✓ ✓ (Chen et al., 2016, 2012;
breast Moghadamtousi et al.,
2014; Wang et al., 2014)
Colon, lung, breast, ✓ ✓ ✓ ✓ ✓ (Ali et al., 2014; Amin
skin et al., 2005; Chatterjee
et al., 2012; El Bairi et al.,
2017)
✓ ✓ ✓
(continued on next page)
Journal of Ethnopharmacology 229 (2019) 54–72
 Table 4 (continued)

Plant (common names) Plant part Major phytochemicals Types of cancer Mechanisms of action References
Traditional uses (s) used present tested
for extract Cell Epigenetic Antioxidant Anti- Inhibition of Apoptosis, Inhibition of cell
cycle modulation inflammatory or pro-survival necrosis or migration and/
A.B. Oyenihi, C. Smith

arrest immune system cell signaling autophagy or angiogenesis

modulation

Raphanus sativus L. (Radish) Root, Prostate, cervical, (Barillari et al., 2008;

Microbial and fungal seed, lung, breast Beevi et al., 2010)
infections sprout
Allium sativum L. (Garlic) Clove Alliin, allicin alliin, alliinase Hepatic, colon, ✓ ✓ ✓ ✓ ✓ (Jikihara et al., 2015; Kim
Antiseptic, diabetes, stomach et al., 2012; Schafer and
gastric ulcers Kaschula, 2014; Shukla
and Kalra, 2007)
Aloe vera (L.) Burm.f. (Aloe Leaf gel Aloe-emodin, emodin, aloin Skin, cervical, ✓ ✓ ✓ (Hussain et al., 2015;
vera) Burns, diabetes, breast, hepatic Saini et al., 2010; Shalabi
bacterial infections, et al., 2015)
constipation
Astragalus membranaceus Root Swainsonine, saponins, Gastric, colorectal, ✓ ✓ ✓ (Auyeung et al., 2012;
(Fisch.) Bunge (Katira) polysaccharides lung Tseng et al., 2016; Wu
Nephritis, diabetes et al., 2017; You et al.,
2012)
Crocus sativus L. (Saffron) Leaf, Safranal, Crocetin, Crocin Lung, breast, ✓ ✓ ✓ ✓ (Bhandari, 2015;
Asthma, coughs flower leukaemia, skin, D'Alessandro et al., 2013;
prostate, cervical, Khorasanchi et al., 2018;
colon, colorectal, Patel et al., 2017)
pancreatic
Ginkgo biloba L. (Maidenhair Leaf, Ginkgolides, Ovarian, breast, ✓ ✓ ✓ ✓ (Ahmed et al., 2017; Cao

65
tree) Dementia, exocarp polysaccharides, proteins colon, liver, lung et al., 2017; Dias et al.,
Alzheimer's disease, 2008; Han et al., 2016;
fatigue Park et al., 2013; Ye et al.,
2007)
Panax ginseng C.A.Mey. Root Ginsenosides, gintonin Lung, skin ✓ ✓ ✓ (Ahuja et al., 2018; Pan
(Ginseng) Tonic et al., 2013; Qi et al.,
2010; Sharma and Goyal,
2015; Wang et al., 2016)
Journal of Ethnopharmacology 229 (2019) 54–72
A.B. Oyenihi, C. Smith
Tables 2 and 3. These reports give experimental credence to the critical
roles of the polyphenol component in many plant extracts for which
anti-cancer effects have been illustrated. For clarity, common names
and traditional uses have been indicated for plants relevant to this re-
view, at their first mention in tables.
To facilitate comparison, the other widely studied medicinal plant
extracts for which their primary anti-cancer qualities have been at-
tributed to major phytochemicals other than polyphenols, are presented
in Table 4.
In terms of study design, treatment duration for in vitro models
(Table 2) are normally of more uniform, short duration − 24 to 72 h for
the majority of reports – as this is sufficient time to assess changes in the
parameters most often assessed. In contrast, in vivo protocols (Table 3)
vary substantially, but this is probably due to cancer type-specific re-
quirements for accurate simulation of cancer progression across various
models. From the tabulated information, it is also evident that although
the dosages used are quite variable across research groups, the biolo-
gical effects reported are indeed very similar. Of further significance,
from a comparison of the information in Tables 1 and 4, for both
polyphenol-containing products and non-polyphenols, the most con-
sistently reported mechanisms are related to apoptosis and cell cycle
arrest. Of interest, the phytochemical substance class “alkaloids” are
abundantly present in most of the non-polyphenol extracts. This poses
two interesting possibilities: firstly, oxidative stress has been linked to
both increased apoptosis (Tor et al., 2014; Xie et al., 2014) and cell
cycle arrest (Queiroz et al., 2014) and secondly, both polyphenols and
at least some alkaloids have been reported to be strong antioxidants,
and importantly, at very low concentrations. One such alkaloid (delta 7-
mesembrenone) was recently shown to have a relatively high risk of
adverse pro-oxidant effect at a higher dose due to its high potency
(Smith, 2018). Similar to other studies reporting oxidative damage after
antioxidant mega-dosing in the context of polyphenols (Chakraborthy
et al., 2014; Liu, 2014; Zhang and Zhang, 2014), higher concentrations
of this alkaloid were also associated with decreased mitochondrial
viability and increased cell death. Thus, it is possible that in the anti-
cancer plant products, the effects on cell cycle arrest and apoptosis may
be the result of a similar “antioxidant overdose” achieved by either
polyphenols or alkaloids within the product.
Other similarities between alkaloids and polyphenols, which may
support this theory, have also been reported. For example, in the con-
text of already approved plant-derived anti-cancer drugs, the camp-
tothecins isolated from Camptotheca acuminate - belonging to the phy-
tochemical class of alkaloids (Moraes et al., 2017) – are primarily DNA
topoisomerase I inhibitors (Hartmann and Lipp, 2006), which is similar
in action to the synthetic polyphenol drugs etoposide and teniposide
already mentioned. Of interest, DNA topoisomerase I inhibition has
been previously been linked to antioxidant treatment (Liu, 2014),
which further supports our theory.
Another noteworthy consideration is that although much progress
has been made in elucidating how these alkaloids and their imitations
may be used for cancer management, their side effects have dis-
couraged extensive use, prompting a call for safer alternatives. In terms
of their safety profiles, polyphenols appear to be better tolerated than
alkaloids (Pirvu, 2014) so it is believed they may offer comparative
advantages for chemoprevention when administered within therapeutic
ranges. Perhaps a consideration at this point should be that natural drug
discovery initiatives focus on the development of safe ranges for anti-
oxidant treatment of cancer, be it by polyphenols or alkaloids, although
polyphenols seem the superior choice at this point.
4. Why are there no registered natural polyphenol medicines?
Despite the many benefits of polyphenol-containing plant extracts
or foods against cancer consistently reported from in vitro, small animal
and even early-phase human clinical trial models, no natural poly-
phenol has been approved or registered for clinical use in the context of
66
Journal of Ethnopharmacology 229 (2019) 54–72
cancer yet (Greenwell and Rahman, 2015; Paller et al., 2016). This is a
testament to the complexities involved in using plant extracts for
medicinal purposes. Firstly, the lack of patentability of medicinal plant
products (without proprietary processing or purification) has dis-
couraged many pharmaceutical companies from investing in the ex-
pensive phase 3 clinical trials required for drug approval, especially
since plant extracts continue to be in demand – albeit at potentially
higher risk to the consumer – even without regulatory approval. Sec-
ondly, without regulations in place to ensure competence and/or dili-
gence of the supplier, there is a high risk of inconsistency in the com-
position and proportion of active ingredients across batches of plant
extracts, that may occur due to variations in manufacturing process, or
weather/soil conditions of raw plant materials, etc. Thirdly, the absence
of appropriate quality control practices, especially in small to medium-
sized enterprises where either human or financial resources are more
limited, complicates the validation of the plant extract standardisation
and consistency in terms of active ingredient proportions and con-
centrations. Fourthly, for most plant extracts, and even well-known
constituents, there is still a relative lack of data on the exact composi-
tion and thus constituent doses of compounds. Differences in cultivation
practices, soil quality and climate may all influence the composition of
a plant and extracts prepared from it. Thus, studies by different groups
(or on extracts from different batches of raw plant material) are quite
difficult to directly compare without phytochemical fingerprinting or
profiling. Lastly, as the focus of most pre-clinical studies is on expected
desired effects in an in vitro setting only, relatively sparse data is
available on potential undesirable effects of doses required for efficacy.
These issues may also be partly culpable for the conflicting results ob-
tained from some clinical trials already conducted. Nonetheless, the
absence of a conventional ‘western’ polyphenol-containing anti-cancer
drug does not affect the global interest in the use of polyphenol-con-
taining plant extracts or foods to combat cancer, although the common
practice currently seems to be using these products in the form of
dietary supplements.
Many researchers in the field of natural medicines have concluded
that a combination therapy of different types of polyphenols or poly-
phenol plus other phytochemicals – as is the case of most medicinal
plant extracts – seems to be a more reliable and safer approach (Aung
et al., 2017; Lewandowska et al., 2014; Niedzwiecki et al., 2016) than
using single isolates. High doses of single polyphenols are usually re-
quired for anti-cancer efficacy in humans, which may increase the risk
of drug toxicity and lend towards the limitations already observed in
most synthetic conventional anti-cancer drugs currently available. In-
deed, a recent review of published breast cancer research suggested that
plant-derived foods or extracts rather than single isolated phytochem-
icals may be a better strategy for clinical management due to the sy-
nergistic or additive effects of the different phytochemicals present
(Kapinova et al., 2017). However, clearly, there is a requirement for
understanding the role of single components. Pharmacologists and
biologists could play an important role in this niche in terms of eluci-
dating individual components contained in plant material and their
individual mechanisms of action. This knowledge may enable better
selection of high quality raw natural plant material, but also pharma-
ceutical compounding, to arrive at a medicine with minimum risk and
maximum benefit to the vulnerable cancer patient.
Thus, understanding what exactly each phytochemical contributes
to the overall medicinal value and optimizing the therapeutic dose of
each component will lead to the standardisation of plant extracts and
probably increase both their efficacy and safety.
5. The way forward: teasing apart plants to elucidate, understand,
compound
Clearly, much work is still to be done in the context of polyphenol
potency and standardisation of doses for the anti-cancer applications.
As already mentioned, medicinal plant extracts are usually mixtures of
A.B. Oyenihi, C. Smith
several phytochemicals, so that separation of the different components
in the matrix is quite a meticulous process. In this section, we provide
some insights into analytical considerations that are vital to the process
of scientific validation of potential health benefits of plant products.
Newer methods of extraction of polyphenols such as the use of ul-
trasound, microwave, supercritical fluid, subcritical water, hydrostatic
pressure, pulsed electric field and so on have been critically reviewed
by Dai and Mumper (2010) and Khoddami et al. (2013). When com-
pared to the more conventional methods of maceration or decoction in
solvents, these methods were shown to more effectively extract the
polyphenol components in the plants as well as the previously termed
“non-extractable polyphenols” (Castro-Lopez et al., 2017). The method
of extraction has a great impact on the pharmacological activities of
polyphenols. For example, the microwave-assisted extraction method
conferred superior antioxidant qualities on several plant extracts in
comparison to other methods used due to higher total phenol contents
in these extracts (Castro-Lopez et al., 2017). Thus, it is imperative to use
appropriate and sufficiently effective extraction methods so that firstly,
mechanisms of action in the raw material is not lost in the process and
secondly, so that elucidated mechanisms of action in isolated actives
are in fact accurate representations of the plant's potential.
Following extraction, spectrophotometric and chromatographic
methods are employed to separate, purify and quantify the different
types of polyphenols present in the plant extract. Spectrophotometry-
based assays such as Folin-Ciocalteu, proanthocyanidin, flavonoid-alu-
minium chloride complexation and potassium iodate methods give only
an estimate of the total amount of phenolics, proanthocyanidins, fla-
vonoids and tannins respectively. However, they do not separate nor
absolutely quantify the individual phytochemicals present in the plant
extract (Ignat et al., 2011; Khoddami et al., 2013). On the other hand,
liquid or gas chromatographic methods allow for separation, purifica-
tion and quantification of the different types of polyphenols, con-
currently offering a major advantage over the spectrophotometric
methods (Ignat et al., 2011; Khoddami et al., 2013). The combination of
high-performance chromatography and mass spectrometry techniques
to separate phytochemicals in plant extracts has particularly re-
volutionised the traditional medicine industry over the past two dec-
ades. The mass spectrometry component allows for the real-time elu-
cidation and structural characterisation of the individual
phytochemicals separated by chromatography thus, saving precious
time and resources. This approach has enabled rapid authentication of
medicinal plant extracts, fruit juices and wines using their characteristic
polyphenolic profiles leading to the timely identification and sub-
sequent removal of ‘adulterants’ (Diaz-Garcia et al., 2013; Fontana and
Bottini, 2014; Pardo-Mates et al., 2017). In addition, the batch-batch
variation in the manufacture of traditional medicines and plant pro-
ducts has been greatly reduced through adequate quality control me-
chanisms formulated by the application of the chromatography-mass
spectrometry techniques. Efforts have been made to continually im-
prove either the chromatography component or the mass spectrometry
component for faster, more efficient and more accurate separation of
polyphenols, as reviewed in recent reports (de Villiers et al., 2016;
Ganzera and Sturm, 2018; Lucci et al., 2017). For instance, the use of
ultra-high pressure, high temperature, monolithic and superficially
porous phases and comprehensive two-dimensional liquid chromato-
graphic systems have enhanced the performance characteristics in the
separation of the polyphenol component in complex matrices (de
Villiers et al., 2016). The application of these chromatographic tech-
niques plus recent mass spectrometry tools such as ion trap, triple
quadrupole, time-of-flight, Orbitrap has yielded an efficient and time-
saving resolution of the diverse polyphenols present in plant extracts
(de Villiers et al., 2016; Lucci et al., 2017). These techniques not only
assist in rapidly distinguishing the polyphenol component in several
plant extracts but also serve as an important screening tool in the
continuing search for novel anti-cancer plant extracts.
67
Journal of Ethnopharmacology 229 (2019) 54–72
6. Conclusion
In conclusion, in our opinion, there is no denying that polyphenols –
and specifically combinations containing multiple different polyphenols
– may be optimised to develop anti-cancer drugs with better risk:
benefit ratio than currently used, conventional anti-cancer medicines.
Despite consistently promising pre-clinical data, more research is re-
quired to understand the synergy between different polyphenols and
potency of individual polyphenols, so that effective doses may be de-
termined through the process of pharmaceutical compounding and
clinical trials. We believe the time has come to move away from just
confirming the traditional medicine claims of polyphenol-containing
plant extracts used in cancer management, and to focus on reducing
patient risk by elucidating potential extract-drug, polyphenol-drug or
polyphenol-polyphenol interactions. Given the near-impossible task of
trying to standardize research protocols in terms of treatment dose and
duration, researchers are urged to employ the most accurate extraction
and characterisation methods available, to ensure that research data
from various sources can be integrated for a holistic interpretation of
polyphenol potency and synergistic action against cancer.
Acknowledgements
None.
Funding
The authors would like to acknowledge the South African National
Research Foundation for a postdoctoral bursary to ABO.
Author contributions
Both authors contributed equally to manuscript preparation and
both authors approved the final version.
Declaration of interest
None.
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