DRUDIS-1530; No of Pages 5

Drug Discovery Today  Volume 00, Number 00  November 2014 PERSPECTIVE

feature
New drugs from ancient natural foods.
Oleocanthal, the natural occurring
spicy compound of olive oil: a brief
history
Morena Scotece1, Javier Conde1, Vanessa Abella1,2, Veronica Lopez1, Jesús Pino3, Francisca Lago4,
Amos B. Smith III5,6, Juan J. Gómez-Reino7,8 and Oreste Gualillo1, oreste.gualillo@sergas.es

Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the

Features  PERSPECTIVE
most ancient known foods and has long been associated with health benefits. Many phenolic
compounds extracted from Olea europea L. have attracted attention since their discovery. Among these
phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for
different diseases, showing relevant pharmacological properties in various pathogenic processes,
including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the
most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention
on its anti-inflammatory and chemotherapeutic roles.

Introduction
The Med diet has been associated with many
beneficial health properties, including lower
incidences of cardiovascular mortality, age-re-
lated cognitive disease, and breast and colon
cancer. This diet is characterized by an elevated
intake of EVOO, fruit, grains, vegetables and
cereals; a moderate intake of fish and poultry; a
low intake of dairy products, red and processed
meats and sweets; and wine in moderation,
consumed with meals [1]. Olive oil, the main lipid
component of the Mediterranean diet, can exert
a host of beneficial biological functions, as
demonstrated by multiple observational studies
as well as by some clinical trials. In addition to
the excellent balance between saturated and
unsaturated fatty acids (oleic acid, a monoun-
saturated fatty acid, was considered to be main
compound responsible for most of the cardio-
protective effects of Med diet), several lines of
evidence have accumulated on the beneficial
properties of minor components of olive oil
minor, particularly the phenolic component,
which show a wide spectrum of bioactive
properties, including antioxidant and anti-in-
flammatory effects, which are both associated
with the origin of many chronic diseases.
Chronic inflammation is a crucial factor in
these pathologies and the attenuation of pro-
inflammatory mediators has been partially at-
tributed to the high intake of EVOO accompa-
nying the Med diet. Phenolic compounds
extracted from EVOO have been shown to have
antioxidant [2], anti-inflammatory [3] and
antithrombotic activities [4]. In addition, olive oil
has been suggested to alleviate cognitive
decline resulting from neurodegeneration [e.g.
Alzheimer’s disease (AD)] [5]. Many of these
phenolic compounds, such as ligstroside and
oleuropein, are responsible for the bitterness,
pungency, and astringency of EVOO [6]. Re-
cently, the European Food Safety Authority
suggested an increase in the consumption of
EVOO polyphenols because these compounds
are able to prevent low-density lipoprotein
(LDL) oxidation [7]. Thus, the increase in con-
sumption of EVOO phenols, without increasing
the total lipid intake, would be beneficial to the
general population and, therefore, should be
recommended by health authorities. However,
phenol-rich EVOOs are bitter and pungent and,
thus, might not be well accepted by those
consumers who prefer sweet oils (such as re-
fined olive oil or seed oils).

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Please cite this article in press as: Scotece, M. et al. New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history, Drug Discov Today
(2014), http://dx.doi.org/10.1016/j.drudis.2014.10.017
 DRUDIS-1530; No of Pages 5
PERSPECTIVE
In 2003, Andrewes et al. identified a com-
pound in EVOO, ( )-decarboxymethyl ligstroside
aglycone, that causes the throat burn charac-
teristic of many EVOOs [6]. This compound had
earlier been isolated by Montedoro et al., but the
characteristic throat burn sensation had not
been identified [8]. Beauchamp et al. then
identified this compound, which they named
oleocanthal (OC) (oleo- for olive, canth- for sting,
and -al for aldehyde) [9]. Importantly, they
reported that OC is a potent anti-inflammatory
compound, which they predicted based on the
sensory property, namely the sting in the throat,
which it shares with another structurally unre-
lated anti-inflammatory drug, ibuprofen. Simi-
larly to ibuprofen, the authors reported that OC
inhibits the cyclooxygenase 1 (COX-1) and COX2
enzymes. They postulated that consumption of
OC over a lifetime might be one of the factors
underlying the health benefits of the Med diet.
Subsequently, the group of Amos Smith
[10,11] completed the first total synthesis of OC
and other analogs, as well as determining the
configuration of the active component. More
recently, the anti-inflammatory activity of oleo-
canthal, and also several of its derivatives, on the
expression of nitric oxide synthase (NOS) type II
in chondrocytes has been examined [12]. In
addition, the anti-inflammatory activities of OC
Features  PERSPECTIVE
were recently confirmed in a study that dem-
onstrated that this compound inhibits others
pro-inflammatory factors, such as macrophage
inflammatory protein (MIP)-1a and interleukin
(IL)-6 in J774 macrophages and ATDC5 chon-
drocytes [13]. In addition to its anti-inflammatory
properties, OC has been shown to exert a potent
antimyeloma activity in vitro, inhibiting the ex-
pression and secretion of MIP-1a in human
multiple myeloma (MM) cells [14]. This com-
pound is also able to alter the oligomeric
structure or function of the neurotoxic b-amy-
loid, counteracting the debilitating effects of AD
[15].
Here, we summarize the current pharmaco-
logical knowledge of the properties of OC.
OC: its chemical structure and syntheses
As noted above, OC, the dialdehydic form of ( )
deacetoxy-ligstroside aglycone (Fig. 1a), was
identified in 2003 by Andrewes and colleagues
as the principal contributor to the back-of-the-
throat astringency commonly associated with
high-quality EVOO [6,16]. Recognizing the need
for a ready source of OC, the group of Smith
reported in 2005 the first total syntheses of both
the (+)- and ( )-enantiomers of OC, confirming
the proposed structure of the olive oil irritant
and also determining its absolute stereochem-
2 www.drugdiscoverytoday.com
Please cite this article in press as: Scotece, M. et al. New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history, Drug Discov Today
(2014), http://dx.doi.org/10.1016/j.drudis.2014.10.017
Drug Discovery Today  Volume 00, Number 00  November 2014
(a)
HO
(b)
R1
R4
FIGURE 1
Chemical Structures. (a) The structure of oleocanthal (OC) compared with that of ibuprofen and
(b) chemical structure of the OC pharmacophore.
istry [10,11]. The method of syntheses and pu-
rification of the ( ) enantiomer of OC was then
patented in 2006 by Smith and colleagues
(CA2607977 A1). The group also provided
functional derivatives of OC, having a general
formula as shown in Fig. 1b. The group of
Estanove also patented a method to enrich an
extract containing OC, leading to a new process
for the extraction of OC from olive oil
(WO2008107557 A1). Although not structurally
related to the nonsteroidal anti-inflammatory
drug (NSAID) ibuprofen (Fig. 1a), OC shares with
ibuprofen its perceptual and anti-inflammatory
properties. In fact, both compounds induce a
similar sensory irritation in the throat and are
able to inhibit efficiently relevant enzymatic
systems of the inflammatory cascade. Therefore,
OC is now acknowledged as a naturally occurring
NSAID [12–14,17]. A recent study showed that
the peppery sting characteristics of both OC and
ibuprofen is likely to be mediated by the acti-
vation of transient receptor potential cation
channel, subfamily A, member 1 (TRPA1) re-
ceptor in the oropharyngeal region [18].
Anti-inflammatory activity of OC
The first evidence for the anti-inflammatory ef-
fect of OC was published by Beauchamp and
colleagues. They reported that, similar to ibu-
profen, which is a potent modulator of inflam-
mation, and an analgesic, OC was able to induce
dose-dependent inhibition of COX-1 and COX-2,
which are involved in the biochemical inflam-
mation pathways supported by arachidonic acid
derivatives [9] (Fig. 2a). Other groups have in-
O
Oleocanthal
O
O CH3
O
CH3
Ibuprofen
CH3 COOH
H3C
X Y
Z R2
A R3
Drug Discovery Today
vestigated the effects of OC and its derivatives
on lipopolysaccharide (LPS)-induced NO pro-
duction in chondrocytes. NO is a gaseous me-
diator of the inflammatory response that is
involved in multiple inflammatory degenerative
diseases [19]. It was shown that OC, as well as its
derivative 231, downregulated nitrite production
and inducible (i)NOS protein expression in LPS-
challenged chondrocytes [12]. More recently, it
was also demonstrated that OC was able to
inhibit the inflammatory mediators, IL-6 and
MIP-1a in murine chondrocytes and in macro-
phages challenged with LPS. In addition,
researchers showed that the anti-inflammatory
actions of OC in macrophages were related to
the inhibition of NO production, via iNOS
downregulation, and also to a decrease of rel-
evant pro-inflammatory cytokines, such as IL-1b
and tumor necrosis factor (TNF)-a [13] (Fig. 2b).
These inflammatory mediators have consider-
able roles in inflammatory-degenerative joint
diseases, such as osteoarthritis and rheumatoid
arthritis. Thus, on the one hand, OC inhibits local
inflammatory activation in cartilage and, the
other hand, it inhibits the inflammatory cascade
in synovial cells. Taken together, these data
suggest that OC could be an interesting thera-
peutic agent for the treatment of degenerative
joint diseases.
Chemopreventive and chemotherapeutic
effects of OC
Several recent studies demonstrated that the
consumption of EVOO reduces the risk of various
types of cancer, including prostate, lung, larynx,
DRUDIS-1530; No of Pages 5

Drug Discovery Today  Volume 00, Number 00  November 2014 PERSPECTIVE

tau fragment K18 in an unspecific manner [29].

(a) Arachidonic acid
The same group showed that OC also exhibited
Oleocanthal Oleocanthal
nonspecific covalent interactions with tau-441,
COX-1 COX-2
inducing a conformational rearrangement,
which could explain the antifibrillogenic ability
of OC [30]. The interaction of beta-amyloid (Ab)
oligomers with neurons also appears to be a
crucial step in the initiation of AD. Pitt and
Anti-inflammatory activity
colleagues reported that low doses of OC were
(b) Chondrocyte Macrophage
able to modulate the structure, immunoreac-
Oleocanthal
tivity, and synaptotoxicity of Ab oligomers,
LPS LPS
suggesting that OC was able to reduce the
formation of Ab senile plaques in the brain [15].
Several lines of evidence in the literature now
report that AD mainly develops as a result of the
NO•, iNOS, NO•, iNOS, excessive accumulation of Ab in the brain be-
MIP1-α, IL-6 MIP1-α, IL-6
TNF-α
cause of its faulty clearance across the blood–
brain barrier (BBB). Two major transport proteins
mediate Ab removal from the brain across the
Anti-inflammatory activity BBB, P-glycoprotein (P-gp) and LDL lipoprotein
Drug Discovery Today
receptor-related protein-1 (LRP1) [31,32]. In this
regard, a recent study by Abuznait demonstrated
FIGURE 2 that OC is able to upregulate P-gp and LRP1
Schematic representation of the general anti-inflammatory activities of oleocanthal. (a) molecular enhancing the clearance of Ab from the brain
pharmacological targets and (b) cellular targets. Abbreviations: COS, cyclo-oxygenase; IL, interleukin; LPS, [33] (Fig. 3).
lipopolysaccharide; iNOS, inducible nitric oxide synthase; MIP, macrophage inflammatory protein; TNF,
tumor necrosis factor.
Concluding remarks
OC represents approximately 10% of the total
ovary, breast, and colon cancers [20–24]. The bone marrow milieu. It was shown that OC phenolic compounds in EVOO, the main source
group of Choi studied the role of OC in HT-29 inhibited the expression and secretion of MIP- of fat in the Med diet, although this percentage

colon cancer cells and suggested that a molec-
ular mechanism mediates the antitumor activity
of OC. They reported that OC was able to inhibit
the activity of activator protein (AP)-1, which is a
transcription factor that controls cellular differ-
entiation, proliferation, and apoptosis. OC also
inhibited cell viability and induced apoptosis in
HT-29 colon cancer cells, activating AMP-acti-
vated protein kinase (AMPK) and inhibiting COX-
2 expression [25]. It is known that the proto-
oncogene receptor kinase c-Met has a significant
oncogenic role in many tumors. A recent study
reported that OC was able to inhibit the phos-
phorylation of c-Met kinase in vitro, suggesting a
possible role for this compound in the control of
c-Met-dependent malignancies [17]. Another
interesting study by Margarucci et al. revealed
relevant effects of OC on heat shock protein
(Hsp)-90, a chaperone with a key role in several
human diseases, particularly cancer and neuro-
degeneration. This group reported a potent ef-
fect of OC as an inhibitor of Hsp90 in human
leukemia monocytes lymphoma U937 cells [26].
The potential antitumor properties of oleo-
canthal have also been elucidated. The role of OC
has been investigated in a paradigmatic plasma
cell malignancy, MM, which causes devastating
bone destruction by activating osteoclasts in the
1a, a factor that has an important role in the
etiology of MM. In addition, it was also dem-
onstrated that OC inhibited MM cell proliferation
by inducing the activation of apoptosis mech-
anisms and by downregulating extracellular-
regulated kinase (ERK)-1/2 and AKT signal
transduction pathways [14]. More recent studies,
for instance those by Akl and colleagues, con-
firmed the anticancer effects of OC treatment in
breast cancer. These authors observed that OC
was able to reduce c-Met kinase activity, cell
growth, migration, and invasion of breast cancer
cells and tumorigenicity in a mouse model [27]
(Fig. 3).
The role of oleocanthal in
neurodegenerative diseases
The high consumption of EVOO has also been
associated with a reduced risk of neurodegen-
erative pathologies, such as AD. In particular, OC
have been found to reduce the fibrillization of
tau protein, which is a microtubule-associated
protein that promotes microtubule assembly.
Lack of this stabilization is associated with the
development of neurofibrillary tangles, which
comprises major hallmark lesions of AD [28]. OC
alters the fibrillization of tau protein by cova-
lently reacting with lysine e-amino groups of the
Features  PERSPECTIVE
varies as a result of the source and quality of
EVOO. Given the known relevant pharmacolog-
ical properties of OC and its involvement in
pathogenic processes, such as oxidative stress,
inflammation, neurodegenerative, and cardio-
vascular diseases, OC continues to attract re-
search attention. The most recent data also
suggest that EVOO, as a main component of the
Med diet, could serve as one of the best sources
of nutraceuticals to introduce with dietary in-
take. In this regard, the recently published evi-
dence for the health benefits associated with the
Med diet [34] is clearly in support of this hy-
pothesis and shows the efficacy of a dietary
intervention, based on the prevalent use of
EVOO as a source of lipids and also in compar-
ison to low-fat dietary intake models. The studies
reported in here suggest a clear beneficial effect
of this compound and indicated a possible role
of OC as therapeutic agent for future treatment
of certain diseases.
However most of these studies have only been
carried out in in vitro systems and, therefore, it is
difficult to extrapolate these conclusions to
whole-body organisms. However, the results
published so far are promising and suggest a
wide spectrum of activity of OC on multiple
diseases. Thus, further research on both in vitro

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Please cite this article in press as: Scotece, M. et al. New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history, Drug Discov Today
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 DRUDIS-1530; No of Pages 5
PERSPECTIVE
CNS
Breast cancer cells
O P
O
O CH3
HO
Oleocanthal O
Colon cancer cells
Features  PERSPECTIVE
Bone marrow
FIGURE 3
Summary of the pharmacological effects of oleocanthal (OC) in cancer cells and neurodegenerative diseases, including a detailed mechanism of OC activity in
multiple myeloma (MM) cells. Abbreviations: CCRS, Chemokine Receptors Please; CNS, central nervous system; ERK, extracellular-regulated kinase; MIP,
macrophage inflammatory protein; RANKL, RANK ligand.
and in vivo systems is warranted. A crucial first
step would be to delineate the mechanisms of
drug action of OC and to determine whether OC
mediates its effects by cell surface receptors or
intracellular targets in tumor and other cells.
In addition, more information relating to the
pharmacokinetics and pharmacodynamics of OC
is needed. At present, no data are available from
clinical studies and it will be necessary to carry out
comprehensive clinical trials on both the pre-
ventive potential as well as curative efficacy of OC
in different disease states before these thera-
peutic claims can be validated. In any case, caution
should be taken to avoid untruthful expectations
of success in using this compound as pharma-
cological agent before clinical trials have been
successfully carried out. Even if preclinical and
clinical trials proceed, the concerns raised previ-
ously must be adequately addressed to maximize
the potential pharmacological activity of OC. As
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Drug Discovery Today  Volume 00, Number 00  November 2014
Oleocanthal MM cells
MIP1 α
CCRS receptors
RANKL
P-P38 AK
P-AKT
P-ERK1/2
•Inhibition of osteoclastic differentiation
and bone destruction
•Inhibition of cell growth and apoptosis
ells
scientists, we are obliged to provide the most
accurate information through our scientific pub-
lications and media; in particular, we have to stress
the limitations of the studies conducted to date,
thus avoiding false hopes of our patients.
In conclusion, the novel insights into the
pharmacology of OC and its derivatives are
providing new perspectives for the treatment of
certain chronic and/or degenerative diseases. A
better understanding of OC pharmacology will
also provide solid rationale for introducing
functional foods, such as EVOO, to improve
integrated dietary strategies that will be of help
in clinical practice.
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6
Monell Chemical Senses Center, Philadelphia, PA,
USA
7
Department of Medicine, University of Santiago de
Compostela, Santiago de Compostela, Spain
8
Servizo Galego de Saude, Instituto de Investigación
Sanitaria de Santiago, Division of Rheumatology,
Santiago University Clinical Hospital, Santiago de
Compostela, Spain

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Please cite this article in press as: Scotece, M. et al. New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history, Drug Discov Today
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