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Citation: Eldesouki, S.; Qadri, R.;
Abu Helwa, R.; Barqawi, H.; Bustanji,
Y.; Abu-Gharbieh, E.; El-Huneidi, W.
Recent Updates on the Functional
Impact of Kahweol and Cafestol on
Cancer. Molecules 2022,27, 7332.
https://doi.org/10.3390/
molecules27217332
Academic Editor: Amr Amin
Received: 19 September 2022
Accepted: 26 October 2022
Published: 28 October 2022
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molecules
Review
Recent Updates on the Functional Impact of Kahweol and
Cafestol on Cancer
Salma Eldesouki 1, Rama Qadri 1, Rashid Abu Helwa 1, Hiba Barqawi 2,3 , Yasser Bustanji 3,4,5 ,
Eman Abu-Gharbieh 2, 3, * and Waseem El-Huneidi 3,4,*
1College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
2Department of Clinical Sciences, College of Medicine, University of Sharjah,
Sharjah 27272, United Arab Emirates
3Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
4Department of Basic Medical Sciences, College of Medicine, University of Sharjah,
Sharjah 27272, United Arab Emirates
5Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan,
Amman 11942, Jordan
*Correspondence: eabugharbieh@sharjah.ac.ae (E.A.-G.); welhuneidi@sharjah.ac.ae (W.E.-H.);
Tel.: +971-65057289 (E.A.-G.); +971-65057222 (W.E.-H.)
Abstract:
Kahweol and cafestol are two diterpenes extracted from Coffea arabica beans that have
distinct biological activities. Recent research describes their potential activities, which include anti-
inflammatory, anti-diabetic, and anti-cancer properties, among others. The two diterpenes have been
shown to have anticancer effects in various
in vitro
and
in vivo
cancer models. This review aims to
shed light on the recent developments regarding the potential effects of kahweol and cafestol on
various cancers. A systematic literature search through Google Scholar and PubMed was performed
between February and May 2022 to collect updates about the potential effects of cafestol and kahweol
on different cancers in
in vitro
and
in vivo
models. The search terms “Kahweol and Cancer” and
“Cafestol and Cancer” were used in this literature review as keywords; the findings demonstrated
that kahweol and cafestol exhibit diverse effects on different cancers in
in vitro
and
in vivo
models,
showing pro-apoptotic, cytotoxic, anti-proliferative, and anti-migratory properties. In conclusion, the
diterpenes kahweol and cafestol display significant anticancer effects, while remarkably unaffecting
normal cells. Our results show that both kahweol and cafestol exert their actions on various cancers via
inducing apoptosis and inhibiting cell growth. Additionally, kahweol acts by inhibiting cell migration.
Keywords: diterpenes; anti-proliferative; cytotoxic; coffee; anticancer; cancer treatment
1. Introduction
Coffee is one of the most widely consumed beverages in the world. This may be
attributed to its desirable stimulatory effect and distinctive taste. Fortunately, coffee’s
constituents were found to have protective functions against many diseases, including type
2 diabetes mellitus, liver cirrhosis, and neurodegenerative disorders [
1
–
6
]. The physiologi-
cally active components of coffee that play this biological role include caffeine, diterpenes,
chlorogenic acids, and melanoidins; their biological properties make them a hot topic
to investigate.
The diterpenes kahweol and cafestol are fat-soluble compounds derived from Coffee
arabica beans [
7
]. They are structural analogues, with the difference of an additional double
bond in the kahweol molecule (Figure 1) [
8
]. Extraction of kahweol and cafestol can be
performed through direct hot saponification (DHS), direct cold saponification (DCS), and
Bligh and Dyer (BD) or Soxhlet (SO) extraction followed by saponification [
9
]. DHS was
reported to be quicker, more efficient, and more economical than the other techniques
for extracting the diterpenes from coffee. Purification can be performed using a flash
Molecules 2022,27, 7332. https://doi.org/10.3390/molecules27217332 https://www.mdpi.com/journal/molecules
Molecules 2022,27, 7332 2 of 15
chromatography column (FCC) packed with flash silica gel, with hexane/ethyl acetate as
the mobile phase [
10
]. The collected fractions can be further identified by high-performance
liquid chromatography with diode array and mass spectrometry detectors (HPLC–DAD–
MS/MS) [
9
]. This method provides a simple characterization of kahweol and cafestol. In
addition, it distinguishes the two molecules by their molecular mass.
Molecules 2022, 27, x FOR PEER REVIEW 2 of 16
and Bligh and Dyer (BD) or Soxhlet (SO) extraction followed by saponification [9]. DHS
was reported to be quicker, more efficient, and more economical than the other techniques
for extracting the diterpenes from coffee. Purification can be performed using a flash chro-
matography column (FCC) packed with flash silica gel, with hexane/ethyl acetate as the
mobile phase [10]. The collected fractions can be further identified by high-performance
liquid chromatography with diode array and mass spectrometry detectors (HPLC–DAD–
MS/MS) [9]. This method provides a simple characterization of kahweol and cafestol. In
addition, it distinguishes the two molecules by their molecular mass.
Figure 1. Chemical structure of (A) Kahweol and (B) Cafestol, created by ChemDraw.
In unfiltered coffee, such as Turkish coffee or espresso, kahweol and cafestol are
found in relatively higher concentrations in comparison to filtered and instant coffee. A
study performed on healthy ileostomy volunteers showed that, upon coffee consumption,
gastric juices break down nearly 30% of kahweol and cafestol, and 64–70% of cafestol and
70–73% of kahweol are absorbed in the small intestine, with minute amounts of glucuron-
idated or sulphated conjugate forms being excreted in the urine [11]. As only about 1% or
less of conjugate cafestol and kahweol is excreted in the urine, the two diterpenes are
likely metabolised further in the body, and there is evidence that cafestol circulates in the
liver and gastrointestinal tract, exerting its effects [12].
Kahweol and cafestol’s role in raising serum lipids is well-documented. The long-
term ingestion of unfiltered coffee has been linked to increased plasma levels of triacyl-
glycerol and low-density lipoprotein (LDL) cholesterol in human subjects, and cafestol
and kahweol are the primary coffee constituents responsible for this effect, with cafestol
exerting a more potent effect than kahweol [13]. Some in vitro studies showed that cafestol
suppressed LDL receptor activity by decreasing its ability to bind, uptake, and degrade
LDL [14]. However, LDL levels were also found to be raised in mice with LDL receptor
knockdown following cafestol administration [15]. Cafestol suppresses enzymes involved
in bile acid synthesis (sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase), provid-
ing an alternate explanation for the rise in cholesterol levels [15].
Emerging evidence has shown that kahweol and cafestol target several pathways to
prevent disease. Their anti-inflammatory effect is prominently displayed by their ability
to regulate several inflammatory mediators, such as ICAM1, MCP1, and IL-8, which are
involved in cardiovascular disease progression [16,17]. In addition, kahweol and cafestol
inhibit osteoclast differentiation and bone resorption, while promoting osteoblast differ-
entiation, thus ameliorating degenerative bone diseases [18,19]. Of the many roles the
diterpenes play, their anti-carcinogenic effect is perhaps the most significant due to the
poor prognosis of many cancers.
Figure 1. Chemical structure of (A) Kahweol and (B) Cafestol, created by ChemDraw.
In unfiltered coffee, such as Turkish coffee or espresso, kahweol and cafestol are found
in relatively higher concentrations in comparison to filtered and instant coffee. A study
performed on healthy ileostomy volunteers showed that, upon coffee consumption, gastric
juices break down nearly 30% of kahweol and cafestol, and 64–70% of cafestol and 70–73%
of kahweol are absorbed in the small intestine, with minute amounts of glucuronidated
or sulphated conjugate forms being excreted in the urine [
11
]. As only about 1% or less
of conjugate cafestol and kahweol is excreted in the urine, the two diterpenes are likely
metabolised further in the body, and there is evidence that cafestol circulates in the liver
and gastrointestinal tract, exerting its effects [12].
Kahweol and cafestol’s role in raising serum lipids is well-documented. The long-term
ingestion of unfiltered coffee has been linked to increased plasma levels of triacylglycerol
and low-density lipoprotein (LDL) cholesterol in human subjects, and cafestol and kahweol
are the primary coffee constituents responsible for this effect, with cafestol exerting a more
potent effect than kahweol [
13
]. Some
in vitro
studies showed that cafestol suppressed
LDL receptor activity by decreasing its ability to bind, uptake, and degrade LDL [
14
].
However, LDL levels were also found to be raised in mice with LDL receptor knockdown
following cafestol administration [
15
]. Cafestol suppresses enzymes involved in bile
acid synthesis (sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase), providing an
alternate explanation for the rise in cholesterol levels [15].
Emerging evidence has shown that kahweol and cafestol target several pathways to
prevent disease. Their anti-inflammatory effect is prominently displayed by their ability
to regulate several inflammatory mediators, such as ICAM1, MCP1, and IL-8, which are
involved in cardiovascular disease progression [
16
,
17
]. In addition, kahweol and cafestol
inhibit osteoclast differentiation and bone resorption, while promoting osteoblast differ-
entiation, thus ameliorating degenerative bone diseases [
18
,
19
]. Of the many roles the
diterpenes play, their anti-carcinogenic effect is perhaps the most significant due to the
poor prognosis of many cancers.
The chemopreventive function of diterpenes can be seen in their ability to induce
phase 2 detoxifying enzymes and anti-oxidant proteins, which prevents early mutagenic
events. Their pro-apoptotic characteristic also contributes to their anti-tumorigenic effects
Molecules 2022,27, 7332 3 of 15
by downregulating anti-apoptotic proteins, such as Bcl-2, Bcl-xL, mcl1, cFLIP, decreasing
the release of cytochrome c and activating caspase enzymes [
20
]. In addition, diterpenes are
also inhibitors of angiogenesis, as their introduction to HMVECs (Human Microvascular
Endothelial Cells) inhibits cell proliferation and migration [21].
This is the first review focusing on the various effects exerted by kahweol and cafestol
on different
in vitro
and
in vivo
cancer models and the pathways involved in the eradi-
cation of such cancers. The current literature primarily focuses on the general bioactivity
and pharmacological effects of these two diterpenes, including their anti-inflammatory,
anti-diabetic and anti-osteoclastogenesis activity, with only a cursory description of their
anticancer effects [
8
]. Thus, this review aims to discuss, in detail, the tumour-suppressive
role both kahweol and cafestol play in various cancer, through apoptosis, inhibition of pro-
liferation and migration, or induction of cytotoxicity. The biochemical pathways through
which these compounds exert their effects on multiple cancers are outlined, and their
potential function in cancer treatment is explored.
2. Kahweol and Cafestol Effects on Several Cancer Cell Lines
Kahweol and cafestol exert anticancer effects on several cancer cell lines. The pathways
through which they exhibit their properties are discussed in this section. Tables 1and 2
summarise the findings.
Table 1.
In Vitro Impact of Kahweol and Cafestol on Cancer Cell Lines (
↑
indicates induction,
↓indicates suppression).
Cancer Type Cell Line Coffee
Derivative Molecular Target Functional Impact Ref.
Mesothelioma
MSTO-211H
cells
H28 cells
Kahweol and
cafestol
↑Bax
↓Bcl-xl
↑Cleavage of Bid,
Caspase-3, and PARP
↓Sp1
↑Kahweol-induced
apoptosis [7]
Lung Adenocarcinoma A549 cells Kahweol
↑Bax
↓Bcl-2
↓Bcl-xl
↑Cleavage of
Caspase-3 and PARP
↓STAT3
↑DNA
fragmentation
↑
Caspase-3-mediated
apoptosis
↑STAT3-mediated
apoptosis
[22]
Non-small Cell Lung Cancer
NCI-H358 cells
NCI-H1299
cells
Kahweol
↓BTF3
↓ERK signalling
pathway
↑Cleavage of PARP
and Caspase-3
↑p27 and p21
↓cyclin D1
↑Bax
↓Bcl-2
↓Bcl-xl
↑Kahweol-induced
apoptosis [23]
Oral Squamous Cancer HN22 cells
HSC4 cells Kahweol
↓Sp1
↑p27 and p21
↓cyclin D1, Mcl-1, and
survivin
↑Cleavage of Bid,
Caspase-3, and PARP
↓Bcl-xl
↑Bax
↑Kahweol-induced
apoptosis [24]
Molecules 2022,27, 7332 4 of 15
Table 1. Cont.
Cancer Type Cell Line Coffee
Derivative Molecular Target Functional Impact Ref.
Prostate Cancer
PC-3
DU145
LNCaP
Kahweol
acetate
Cafestol
↑Caspase-3 cleavage
↑PARP cleavage
↓Bcl-2
↓Bcl-xL
↓AR
↓CCL2-CCR2
↓CCL5-CCR5
↓Proliferation
↓Migration
↑Apoptosis
[25]
Breast Cancer
MDA-MB231
ZR75-1
MCF-7
Kahweol
↑Caspases-3/7, 9
↑Cytochrome C
↑H2O2
↓Proliferation
↑Apoptosis
↑H2O2 cytotoxicity
[26]
MDA-MB231 Kahweol
↑Caspases-3/7, 9
↑Cytochrome C
↑p-AKT
↑ERK
↓MMP-9
↓uPA
↑Apoptosis
↓Migration
↓ECM remodelling
[26]
SKBR3MCF-
10A Kahweol
↑PARP cleavage via ↑
caspase 3
↓HER2 via ↑PEA3
and ↓AP-2
↓FASN via
↓SREBP-1c, ↓p-Akt
↓cyclin D1 via ↓
mTOR, ↓GSK-3β
↑Apoptosis
↑Cytotoxicity
↓Proliferation
[27]
Colorectal Cancer
HCT116
SW480
LoVo
HT-29
Kahweol ↑PARP cleavage via ↑
ATF3 ↑Apoptosis [28]
HCT116 SW480 Kahweol ↓cyclin D1 via
↑Thr286 ↓Proliferation [29]
HT-29 Kahweol
↑Caspase-3 cleavage
↑PARP cleavage
↓Bcl-2
↓p-AKT
↓HSP40, HSP70,
HSP90
↑Apoptosis
↓Proliferation [20,30]
HT-29 Kahweol
↑Caspase-3
↑PARP cleavage
↓Bcl-2
↓p-AKT
↓HSP-70
↑Apoptosis
↑Cytotoxicity [31]
Renal Carcinoma
Caki Cells Kahweol
↓Bcl-2
↓c-FLIP
↑Cleavage of PARP
↑DEVDase
↑TRAIL-mediated
apoptosis [32]
Caki Cells Kahweol ↑PUMA via ↑CHOP
↑DEVDase
↑p53-independent
apoptosis
↑ER stress-mediated
apoptosis
[33]
Molecules 2022,27, 7332 5 of 15
Table 1. Cont.
Cancer Type Cell Line Coffee
Derivative Molecular Target Functional Impact Ref.
Renal Carcinoma
Caki cells
ACHN cells
A498 cells
Kahweol ↓Mcl-1
↓c-FLIP
↑Caspase-mediated
apoptosis [34]
Caki cells Cafestol
↓Mcl-1
↓c-FLIP
↓MMP
↑Cytochrome C
↑Caspase-3
↓Bcl-2, Bcl-xL, Mcl-1,
c-FLIP
↓PI3K/Akt pathway
↑Mitochondrial
damage
↑Apoptosis
[20]
Caki-1 cells
ACHN cells
Kahweol
acetate and
cafestol
↓Akt and ERK
phosphorylation
↓CCR2, CCR5 &
CCR6↓PD-L1
↓Migration
↓Proliferation
↓Epithelial-
mesenchymal
transition
↑Apoptosis
[35]
Caki cells Cafestol
↑Cleavage of PARP
↑Caspase-3 activity
↓Mcl-1
↑PUMA and Bim
↑ABT-737-mediated
apoptosis [36]
Hepatocellular Carcinoma
Hep3B cells
SNU182 cells
SNU423 cells
Kahweol
↑Cleavage of PARP
and caspase 3
↓p-Src
↓expression of p-Akt,
p-mTOR, p-p70S6K,
and p-4EBP1
↓p-STAT3
↑Kahweol-induced
apoptosis [37]
Leukemia
U937 cells Kahweol
↑Caspase 3
↑Cytochrome C release
↓Bcl-2, Bcl-xL, Mcl-1, XIAP
↓Akt pathways
↑JNK pathways
↑Apoptosis [38]
NB4, K562,
HL60 and KG1
Cafestol
Ara-C
↑Caspase 3
↑CD11b and CD15
↑Apoptosis
↓ROS (Reactive
Oxygen Species)
production by
organelles
↓Clonogenic
potential
[39]
K562 Kawheol and
cafestol
↑Granzyme B via ↑ATF-2, c-Jun, and
CREB phosphorylation ↑Cytolysis [40]
Fibrosarcoma HT-1080 cells Kahweol
acetate
↓PMA-induced MMP-9 via ↓NF-κB
↓Akt/JNK1/2/p38 MAPK
phosphorylation
↓PMA-induced
proliferation,
invasion, and
migration
[30]
Head and Neck
Squamous Cell
carcinoma
SCC25
CAL27
FaDu
Cafestol
Cisplatin No mention of any pathway ↑Apoptosis [41]
Molecules 2022,27, 7332 6 of 15
Table 2.
In Vivo Impact of Kahweol and Cafestol on Cancer models (
↑
indicates induction,
↓
indicates suppression).
Cancer Type Animal Model Cell Line Kahweol/Derivative Molecular Target Functional
Impact Ref.
Prostate Cancer SCID mice DU-145 Kahweol acetate
↑Caspase-3 cleavage
↑PARP cleavage
↓Bcl-2
↓Bcl-xL
↓AR
↓CCL2-CCR2
↓CCL5-CCR5
Inhibition of
tumour growth [25]
Renal cell
carcinoma
BALB/c-nude
mice Caki cells Cafestol
↑Cleavage of PARP
↑caspase-3 activity
↓Mcl-1
↑PUMA and Bim
↑ABT-737-
mediated
apoptosis
[39]
2.1. Lung Cancer
Kahweol and cafestol were tested
in vitro
against different lung cancer cell lines, and
kahweol-induced apoptosis was observed in all cell lines. With regard to mesothelioma,
MSTO-211H cells and H28 cells were examined [
7
]. The apoptosis of cancerous cells was
activated by the upregulation of Bax, alongside the downregulation of Bcl-xL by kahweol
and the cleavage of Bid, caspase-3, and PARP by cafestol. Kahweol’s effects were also tested
on the lung adenocarcinoma cell line A549, demonstrating DNA fragmentation effects and
apoptosis, a decrease in STAT3 expression, as well as an increase in caspase-3 cleavage [
22
].
Finally, non-small cell lung cancer was also tested, specifically, the cell lines NCI-H358
and NCI-H1299 [
23
]. Apoptosis induced by kahweol was achieved, overall, through a
very similar molecular targeting that seems to be common between mesotheliomas, lung
adenocarcinomas, and non-small cell lung cancers and that involves an increase in the
cleavage of both PARP and caspase-3, eventually leading to apoptosis.
2.2. Oral Squamous Cancer
The oral squamous cancer cell lines HN22 and HSC4 were used to help assess the
effects of kahweol in an
in vitro
environment [
24
]. Suppression of the transcription factor
Sp1, which helps in cell differentiation, cell growth, apoptosis, response to DNA damage,
and chromatin remodelling, helped achieve cancer cell apoptosis induced by kahweol.
2.3. Prostate Cancer
The
in vitro
impact of kahweol acetate and cafestol was assessed in the human prostate
cancer cell lines PC-3, DU145, and LNCaP [
25
]. Kahweol acetate and cafestol significantly
inhibited proliferation and migration in addition to enhancing apoptosis in the cell lines.
Cleaved caspase-3 and its downstream target cleaved PARP, both pro-apoptotic proteins,
were upregulated in all cell lines, while the anti-apoptotic proteins STAT3, Bcl-2, and Bcl-xL
were diminished. Androgen receptor (AR), a strong driver of proliferation in prostate
cancer, was downregulated following the treatment with kahweol acetate and cafestol.
Moreover, the levels of CCL-2 and CCL-5, in addition to those of their receptors CCR-2 and
CCR-5, were decreased.
Kahweol acetate and cafestol also exhibited anti-oncogenic activity
in vivo
. In a
xenograft study where human cell lines DU-145 were injected in SCID mouse models,
the oral intake of kahweol and cafestol significantly reduced tumour growth.
2.4. Breast Cancer
Kahweol has been shown to exert an anti-tumour effect on breast cancer cell lines.
In vitro
treatment of MDA-MB231 with kahweol resulted in the inhibition of cell prolifera-
tion along with the induction of apoptosis [
26
]. The levels of the pro-apoptotic proteins
Molecules 2022,27, 7332 7 of 15
caspase-3/7 and 9, as well as of the haemeprotein cytochrome c, were increased by kah-
weol treatment. Kahweol also led to an increase in H
2
O
2
cytotoxicity in a dose-dependent
manner [26].
Kahweol’s effects on the MDA-MB231 cell line can be traced back to the increased
levels of phosphorylated Akt (p-Akt) and extracellular-signal-regulated kinase (ERK), acti-
vating a signalling pathway that regulates multiple cellular processes such as proliferation
and apoptosis [
26
]. The migratory ability of the cell line was also investigated following
kahweol treatment, showing reduced levels of matrix metalloproteinase-9 (MMP-9) and
urokinase-type plasminogen activator (uPA).
Kahweol treatment resulted in reduced proliferation and increased apoptosis in the
HER2-overexpressing SKBR3 cell line [
27
]. It also led to the downregulation of HER2,
a growth factor essential to proliferation. To evaluate kahweol’s effect on HER2, two
molecular targets were assessed: PEA3, which is a suppressor of HER2 transcription, and
AP-2, which upregulates HER2. Kahweol treatment increased the levels of PEA3 while
reducing those of AP-2, confirming that the two pathways were targeted by kahweol. In
addition, fatty acid synthase (FASN), normally elevated in HER2-overexpressing breast
cancers, was decreased in concentration, which was attributed to kahweol’s modulation
of sterol regulatory element-binding protein-1c (SREBP-1c) activity. Kahweol also led to a
reduction in the levels of p-Akt and of its downstream targets mTOR and cyclin D1, which
had an additional impact on the downregulation of FASN [27].
2.5. Colorectal Cancer
Colorectal cancer cell lines have also been shown to be susceptible to kahweol. Kah-
weol induced apoptosis in HCT116 cells
in vitro
through the overexpression of ATF3, which
is mediated by CREB1, ERK1/2, and GSK3
β
[
28
]. In addition, kahweol suppressed the
proliferation
in vitro
of HCT116 and SW480 cells, as evidenced by their reduced levels
of cyclin D1, a cell cycle protein that promotes progression through the cell cycle [
29
].
Kahweol-mediated degradation of cyclin D1 was achieved through the phosphorylation of
cyclin D1 at threonine-286 (Thr286). This effect was attenuated upon the inhibition of any
of kahweol’s molecular targets ERK1/2, JNK, and GSK3β.
Kahweol’s anti-apoptotic characteristics were also observed in the human colon ade-
nocarcinoma HT-29 cells [
30
,
31
]. Cell death was induced by kahweol treatment in a dose-
dependent manner, which was further proven by the elevation of the pro-apoptotic markers
cleaved caspase-3 and PARP, as well as the reduction of the anti-apoptotic markers Bcl-2
and p-AKT. Furthermore, the levels of heat shock proteins (HSP40, HSP70, and HSP90)
were diminished following kahweol treatment. HSPs are a family of molecular chaperones
that prevent cell death, and their downregulation is associated with increased cytotoxicity
of tumour cells.
2.6. Renal Carcinoma
Kahweol’s anti-tumour properties were assessed in several renal carcinoma cell lines
in vitro
, with a predominant focus on Caki cells. TRAIL, a natural ligand for death receptors
found on cancer cells, exerted its apoptotic function on Caki cells more effectively when it
was combined with kahweol [
33
]. Co-treatment with TRAIL and kahweol strongly activated
DEVDases and reduced the levels of c-FLIP and Bcl-2, which are anti-apoptotic proteins.
The JNK and p38 MAPK pathways were found to mediate these effects. Similarly, the
treatment of Caki cells with melatonin and kahweol exhibited comparable findings, which
included the induction of apoptosis and the activation of DEVDases [
32
]. The levels of the
pro-apoptotic Bcl-2 protein from the p53 Upregulated Modulator of Apoptosis (PUMA)
protein family were also upregulated in response to the treatment. This upregulation was
achieved through the C/EBP homologous protein (CHOP), a pro-apoptotic transcription
factor. Furthermore, co-treatment with kahweol and sorafenib, a tyrosine kinase inhibitor,
had analogous effects on renal carcinoma cells [
34
]. Caspase-dependent apoptosis and
Molecules 2022,27, 7332 8 of 15
downregulation of c-FLIP and Mcl-1 were induced by those compounds when tested on
Caki cells as well as on other renal carcinoma cell lines, including A498 and ACHN cells.
Cafestol was also shown to exhibit its anti-carcinogenic effect in renal Caki cells.
Cafestol-induced apoptosis was found to be mediated by the activation of caspase-2 and 3,
the upregulation of the pro-apoptotic proteins Bim and Bax, and the downregulation of
anti-apoptotic proteins, including c-FLIP, Bcl-2, Mcl-1, and Bcl-xL [
31
]. The apoptotic effect
was also achieved by the inhibition of both STAT3 activation and the PI3K/Akt pathway.
The combined anti-tumour activity of kahweol acetate and cafestol was documented in
renal Caki and ACHN cell lines [
35
]. In these cells, the induction of apoptosis and epithelial–
mesenchymal transition upon administration of the diterpenes inhibited proliferation and
migration. The inhibition of STAT3 activation and the downregulation of Bcl-2- and Bcl-xL-
mediated the apoptosis was exerted by the diterpenes, alongside the upregulation of Bax.
Moreover, the diterpenes inhibited Akt and ERK phosphorylation, which are both known
to accelerate metastasis and tumour growth.
Finally, cafestol was tested on the Caki cells both
in vitro
and
in vivo
using BALB/c-
nude mice as the cancer cells recipients [
36
]. Anti-cancer effects were induced via the
synergistic impacts of cafestol and ABT-737, a Bcl-2 family inhibitor. The inactivation of
Bcl-2 proteins (Bcl-2, Bcl-xL, and Bcl-w) helped induce apoptosis. PARP cleavage was
also increased by the combined actions of cafestol and ABT-737. Mcl-1 protein was also
downregulated by this combination in the
in vivo
setting, leading overall to a pro-apoptotic
effect on Caki cells.
2.7. Leukaemia
The U937 leukaemia cell line was tested on
in vitro
to evaluate kahweol’s apoptotic
effect
,
which was found to be mediated by the activation of caspase-3 and the downregulation of
Bcl-2 [38]. The AKT and JNK pathways were also found to be associated with this effect.
Other cell lines such as NB4, K562, HL60, and KG1 were also tested
in vitro
using
cafestol and Ara-c, which is an anti-leukemic agent that was used as a positive control [
39
].
Increased caspase-3 cleavage was observed in HL60 cells, which helped induce apoptosis
via cafestol. Finally, cafestol also helped increase the expression of CD15 and CD11b and
decrease the formation of ROS.
Kahweol and cafestol were also shown to enhance the activity of the NK cell line KHYG-
1 and its cytolytic effect on the NK-sensitive leukaemia cell line K562. The two diterpenes
increased granzyme B expression in NK cells, likely through the phosphorylation of ATF-2,
c-Jun, and CREB, transcription factors involved in the regulation of granzyme B. The net result
was the enhancement of the cytolytic activity of NK cells in leukaemia cell lines [40].
2.8. Fibrosarcoma
Kahweol acetate was found to attenuate cancer formation, proliferation, and migration
by the fibrosarcoma HT-1080 cell line by inhibiting MMP-9, which is usually upregulated
by PMA, 12-phorbol 13-myristate acetate, a synthetic compound known for its oncogenic
effect [
30
]. Kahweol acetate was found to act by inhibiting MMP-9, which is usually
upregulated by PMA. This inhibition was achieved by the suppression of PMA-induced
NF-
κ
B activity, alongside the suppression of the Akt, p38 MAPK, and JNK1/2 signalling
pathways, which were also found to activate MMP-9.
2.9. Hepatocellular Carcinoma
In vitro
, kahweol exerted apoptotic effects as well as inhibited cell proliferation in the
hepatocellular carcinoma cell lines Hep3B, SNU182, and SNU42 [
37
]. The Src signalling
pathway, which is activated upon the phosphorylation of Src, is highly functional in HCC.
The Src pathway was blocked by kahweol by inhibiting the expression of p-Akt, p-mTOR,
p-p70S6K, and p-4EBP1 in Hep3B and SNU182 cells. This had a direct apoptotic and
anti-proliferative effect on the cancer cells. mTOR, which has a proliferative function, was
Molecules 2022,27, 7332 9 of 15
also inhibited by kahweol. Finally, STAT3 was also blocked by kahweol, which induced a
pro-apoptotic effect in the HCC cell lines.
2.10. Head and Neck Squamous Cell Carcinoma
Upon the addition of cafestol
in vitro
, the cell lines of SCC25, CAL27 and FaDu were
found to undergo apoptosis in a dose-dependent manner. When combined with cisplatin,
cafestol displayed an antagonistic effect in all cell lines; moreover, its addition to radiation
therapy showed an additive effect in the cell lines SCC25 and CAL27 [
41
]. Very limited
studies have been performed on head and neck squamous cell carcinoma, which calls for
more extensive research on the topic.
3. Conclusions and Future Perspectives
Diterpenes are fat-soluble compounds that can be derived from Coffea arabica beans
and are known for their disease-preventing characteristics. Kahweol and cafestol, two
diterpenes, were found to have a striking role in preventing the progression of several
types of cancer, as discussed above. This effect is achieved mainly by inducing apoptosis,
alongside cytotoxicity and mitochondrial damage, which are mediated by targeting certain
downstream molecules and pathways, as summarised in Figure 2.
Molecules 2022, 27, x FOR PEER REVIEW 9 of 16
The Src pathway was blocked by kahweol by inhibiting the expression of p-Akt, p-mTOR,
p-p70S6K, and p-4EBP1 in Hep3B and SNU182 cells. This had a direct apoptotic and anti-
proliferative effect on the cancer cells. mTOR, which has a proliferative function, was also
inhibited by kahweol. Finally, STAT3 was also blocked by kahweol, which induced a pro-
apoptotic effect in the HCC cell lines.
2.10. Head and Neck Squamous Cell Carcinoma
Upon the addition of cafestol in vitro, the cell lines of SCC25, CAL27 and FaDu were
found to undergo apoptosis in a dose-dependent manner. When combined with cisplatin,
cafestol displayed an antagonistic effect in all cell lines; moreover, its addition to radiation
therapy showed an additive effect in the cell lines SCC25 and CAL27 [41]. Very limited
studies have been performed on head and neck squamous cell carcinoma, which calls for
more extensive research on the topic.
3. Conclusions and Future Perspectives
Diterpenes are fat-soluble compounds that can be derived from Coffea arabica beans
and are known for their disease-preventing characteristics. Kahweol and cafestol, two
diterpenes, were found to have a striking role in preventing the progression of several
types of cancer, as discussed above. This effect is achieved mainly by inducing apoptosis,
alongside cytotoxicity and mitochondrial damage, which are mediated by targeting cer-
tain downstream molecules and pathways, as summarised in Figure 2.
Figure 2. A diagram summarising the potential anti-cancer mechanisms of kahweol and cafestol in
different cancer cell lines. Created by BioRender.com.
Figure 2.
A diagram summarising the potential anti-cancer mechanisms of kahweol and cafestol in
different cancer cell lines. Created by BioRender.com.
Figure 3portrays the most common molecular targets of kahweol and cafestol, through
which they exhibit their tumour-suppressive function. The two diterpenes, as depicted in
the figure, either upregulate anti-cancer pathways, such as c-PARP and c-caspase, leading
Molecules 2022,27, 7332 10 of 15
to the apoptosis of cancer cells, or downregulate molecules, including Bcl-2 and Bcl-xL,
which also achieves an apoptotic effect.
Molecules 2022, 27, x FOR PEER REVIEW 10 of 16
Figure 3 portrays the most common molecular targets of kahweol and cafestol,
through which they exhibit their tumour-suppressive function. The two diterpenes, as de-
picted in the figure, either upregulate anti-cancer pathways, such as c-PARP and c-
caspase, leading to the apoptosis of cancer cells, or downregulate molecules, including
Bcl-2 and Bcl-xL, which also achieves an apoptotic effect.
Figure 3. The diagram summarises kahweol and cafestol’s effects on anticancer pathways, including
migration, proliferation, and apoptosis. Created by BioRender.com.
Anticancer properties can also be exerted by other diterpenes and their derivatives.
Taxanes, a well-known group of chemotherapeutic agents, are a class of diterpenes ex-
tracted from the plant genus Taxus, indicated for the treatment of breast, ovarian, and
prostate cancers, among others [42]. Another diterpene, triptolide, has long been held as
a promising anticancer agent [43]. It possesses anti-proliferative and pro-apoptotic prop-
erties, inducing cell apoptosis through the upregulation of cleaved caspase-3, cleaved
caspase-9, cleaved PARP, and Bax and the downregulation of Bcl-2, in a similar way as
kahweol and cafestol [44].
The chemotherapeutic role of both diterpenes is mainly exerted in cancer cell lines,
with a possible minimal effect on normal body cells. The anticancer effects of these diter-
penes are dose-dependent and time-dependent. According to the current literature, the
doses of kahweol and cafestol required to exert their anticancer properties are, depend-
ent on the type of cancer and cell line. For example, kahweol suppressed proliferation and
promoted apoptosis in lung adenocarcinoma A549 cells at a dose of 10–40 μM when ad-
ministered for 24 to 48 h [22]. Similarly, an in vitro study reported that 20–80 μM cafestol
inhibited human umbilical vein endothelial cells (HUVEC) proliferation in a dose-de-
pendent manner, ultimately achieving cafestol’s anti-angiogenic effects [8]. The precise
impact of cafestol and kahweol on normal body cells has not been thoroughly studied and
thus warrants further investigation in order to accurately determine the toxicity of these
compounds.
Figure 3.
The diagram summarises kahweol and cafestol’s effects on anticancer pathways, including
migration, proliferation, and apoptosis. Created by BioRender.com.
Anticancer properties can also be exerted by other diterpenes and their derivatives.
Taxanes, a well-known group of chemotherapeutic agents, are a class of diterpenes ex-
tracted from the plant genus Taxus, indicated for the treatment of breast, ovarian, and
prostate cancers, among others [
42
]. Another diterpene, triptolide, has long been held as a
promising anticancer agent [
43
]. It possesses anti-proliferative and pro-apoptotic properties,
inducing cell apoptosis through the upregulation of cleaved caspase-3, cleaved caspase-9,
cleaved PARP, and Bax and the downregulation of Bcl-2, in a similar way as kahweol and
cafestol [44].
The chemotherapeutic role of both diterpenes is mainly exerted in cancer cell lines,
with a possible minimal effect on normal body cells. The anticancer effects of these diter-
penes are dose-dependent and time-dependent. According to the current literature, the
doses of kahweol and cafestol required to exert their anticancer properties are, dependent
on the type of cancer and cell line. For example, kahweol suppressed proliferation and pro-
moted apoptosis in lung adenocarcinoma A549 cells at a dose of 10–40
µ
M when adminis-
tered for 24 to 48 h [
22
]. Similarly, an
in vitro
study reported that 20–80
µ
M cafestol inhibited
human umbilical vein endothelial cells (HUVEC) proliferation in a dose-dependent manner,
ultimately achieving cafestol’s anti-angiogenic effects [
8
]. The precise impact of cafestol
and kahweol on normal body cells has not been thoroughly studied and thus warrants
further investigation in order to accurately determine the toxicity of these compounds.
Compared to the anticancer doses of kahweol and cafestol, their anti-inflammatory
doses are lower. Both diterpenes can inhibit the production of PGE2 and NO, two inflamma-
tory modulators, in lipopolysaccharide (LPS)-activated macrophages in a dose-dependent
manner [8]. For instance, at a dose of 0.5–10 µM, kahweol and cafestol can inhibit the acti-
vation of I
κ
B kinase (IKK), which is the main activator of the inflammatory transcription
Molecules 2022,27, 7332 11 of 15
factor NF-
κ
B, in LPS-activated macrophages [
45
]. Furthermore, at the small dose of 0.5
µ
M,
kahweol can potently inhibit cyclooxygenase-2 (COX-2), which is an enzyme that increases
the levels of the inflammatory modulators PGE2 and NO [45].
Alongside their potent anti-inflammatory roles, kahweol and cafestol’s anti-oxidant
effects are also prominent. The diterpenes exhibit the ability to induce the Keap1/Nrf2/ARE
signalling pathway, which is primarily responsible for protection against reactive oxygen
species within the liver cells [
8
]. This activity, like its anti-inflammatory function, is dose-
dependent. Lee et al. highlighted the diterpenes’ anti-oxidant ability by using them to treat
tetrachloride-induced liver damage in mice [
46
]. By scavenging free radicals and limiting
lipid peroxidation, the diterpenes were able to suppress liver damage, starting from a
dose of 20
µ
M. At higher doses of 100
µ
M and 200
µ
M, liver injury was further decreased.
Unfortunately, this study was conducted in 2007 [
46
], and no recent literature highlights
any advancements regarding the diterpenes’ anti-oxidant effects, making it an interesting
topic to revisit.
Diterpenes have also been utilised in the treatment of other diseases. Vitamin A, a
lipid-soluble diterpene, is a dietary supplement that is essential for human health, as it
has functions in vision, early growth and development, as well as higher brain functions
such as learning and memory [
47
]. Moreover, Vitamin A is used to produce Tretinoin, an
FDA-approved drug that is indicated for the treatment of acne vulgaris, psoriasis, and
cutaneous warts [
48
]. Interestingly, it has also been shown to induce remission in patients
with acute promyelocytic leukaemia. Phytol is a diterpene alcohol that, along with its
derivatives, displays a multitude of biological functions, such as anxiolytic, antimicrobial,
anti-inflammatory, and immune-modulating effects [
49
]. Vitamin K1 can be extracted from
phytol and used in the treatment of clotting factor disorders [50,51].
In conclusion, this review provides sufficient evidence portraying the anticancer role
of kahweol and cafestol
in vitro
and
in vivo
. Inhibition of proliferation and the induction
of apoptosis are the primary mechanisms by which the two diterpenes exert their tumour-
suppressive effects. The literature surrounding
in vitro
studies is impressive, especially
in regard to renal cell carcinoma, breast cancer, leukaemia, and colorectal cancer, as the
tumour-suppressive effects of kahweol and cafestol were verified in numerous studies.
Other cancer cell lines, including mesothelioma, lung adenocarcinoma, non-small cell lung
cancer, oral squamous cancer, prostate cancer, hepatocellular carcinoma, fibrosarcoma, and
head and neck squamous cell carcinoma, were tested using the two diterpenes in no more
than two
in vitro
studies. Prostate cancer and renal cell carcinoma cells are the only cell
lines used in
in vivo
studies, which confirmed their potential response to kahweol and
cafestol, calling for a more extensive clinical investigation. As such, the chemotherapeutic
function of these diterpenes should be assessed alongside their pharmacokinetics, including
their absorption, bioavailability, metabolism, and elimination, as well as their safety profile
via toxicological testing. The two diterpenes have a promising potential to revolutionise
the field of cancer treatment.
4. Methods
A systematic literature search was conducted in the databases PubMed and Google
Scholar between February 2022 and May 2022. The search terms were “Kahweol and
Cancer” and “Cafestol and Cancer”. Each term was searched separately on both databases,
and the articles whose title or abstract was found to be relevant were filtered based on the
inclusion criteria. The researchers independently selected the articles that discussed the
effect of kahweol and cafestol on human cancer cell lines
in vivo
and
in vitro
and discarded
the articles that did not discuss the anticancer effects of the two diterpenes. Figure 4
summarises the data collection process.
Molecules 2022,27, 7332 12 of 15
Molecules 2022, 27, x FOR PEER REVIEW 12 of 16
discarded the articles that did not discuss the anticancer effects of the two diterpenes.
Figure 4 summarises the data collection process.
Figure 4. The flowchart represents the data collection process, including the used databases (Pub-
Med and Google Scholar), the keywords, and the number of included and excluded articles.
Author Contributions: H.B., E.A.-G. and W.E.-H. contributed to conceptualisation and methodol-
ogy, S.E., R.Q. and R.A.H. contributed to the initial writing of the review. Editing was performed
by H.B., Y.B., E.A.-G. and W.E.-H. All authors have read and agreed to the published version of the
manuscript.
Funding: This research was funded by the College of Research and Graduate Studies, University of
Sharjah (Grant number [2001090271] and Grant No. [2001090185].
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: The authors declare no conflict of interest
Abbreviations
AP-2
Activator Protein 2
AR
Androgen Receptor
ATF3
Cyclic AMP-dependent transcription factor
BALB/c-nude mice
Bagg and Albino/c-nude mice
Bax
BCL2-Associated X Protein
Bcl-2
B-cell leukemia/lymphoma 2 protein.
Bcl-xL
B-cell lymphoma-extra large
Bid
BH3 interacting-domain death agonist
Bim
Bcl-2-like protein 11
BTF3
Basic transcription factor 3
Figure 4.
The flowchart represents the data collection process, including the used databases (PubMed
and Google Scholar), the keywords, and the number of included and excluded articles.
Author Contributions:
H.B., E.A.-G. and W.E.-H. contributed to conceptualisation and methodology,
S.E., R.Q. and R.A.H. contributed to the initial writing of the review. Editing was performed by
H.B., Y.B., E.A.-G. and W.E.-H. All authors have read and agreed to the published version of the
manuscript.
Funding:
This research was funded by the College of Research and Graduate Studies, University of
Sharjah (Grant number [2001090271] and Grant No. [2001090185].
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
AP-2 Activator Protein 2
AR Androgen Receptor
ATF3 Cyclic AMP-dependent transcription factor
BALB/c-nude mice Bagg and Albino/c-nude mice
Bax BCL2-Associated X Protein
Bcl-2 B-cell leukemia/lymphoma 2 protein.
Bcl-xL B-cell lymphoma-extra large
Bid BH3 interacting-domain death agonist
Bim Bcl-2-like protein 11
BTF3 Basic transcription factor 3
CCL2-CCR2 Chemokine (C-C motif) ligand 2-CC chemokine receptor 2
CCL5-CCR5 Chemokine (C-C motif) ligand 5-CC chemokine receptor 5
CCR6 CC chemokine receptor 6
CD11b Cluster of differentiation 11b
CD15 Cluster of differentiation 15
cFLIP Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory
protein
Molecules 2022,27, 7332 13 of 15
CHOP C/EBP Homologous Protein
DEVDase Caspase-3-like proteases
ECM Extra-cellular Matrix
ER Endoplasmic Reticulum
ERK signaling Extracellular signal-regulated kinase
FASN Fatty Acid Synthase
FDA Food and Drug administration
GSK-3βGlycogen synthase kinase-3 beta
HER2 Human epidermal growth factor receptor 2
HMVECs Human microvascular endothelial cell-1
HSP40/70/90 Human Heat shock protein 40/70/90
ICAM1 Intercellular adhesion molecule 1
IL-8 Interleukin-8
JNK Jun N-terminal kinase
LDL Low-density Lipoprotein
MAPK Mitogen-activated protein kinase
mcl1 Myeloid cell leukemia-1
MCP1 Monocyte chemoattractant protein-1
MMP-9 Matrix metallopeptidase 9
mTOR Mammalian target of rapamycin
NK-kB nNuclear factor kappa light chain enhancer of activated B cells
p-4EBP1 Phosphorylated eukaryotic translation initiation factor
p-AKT Phosphorylated Protein kinase B
PARP Poly-ADP ribose polymerase
PD-L1 Programmed death-ligand 1
PEA3 Polyoma enhancer activator 3
PI3K/Akt pathway Phosphatidylinositol 3-kinase/Protein kinase B
PMA Phorbol 12-myristate 13-acetate
p-mTOR Phosphorylated mammalian target of rapamycin
p-p70S6K Phosphorylated Ribosomal protein S6 kinase beta-1
p-Src Phosphorilated sarcoma
p-STAT3 Phosphorylated signal transducer and activator of transcription 3
PUMA p53-upregulated modulator of apoptosis
ROS Reactive oxygen species
SCID mice Severe combined immunodeficiency mice
Sp1 Specificity protein 1
SREBP-1c Sterol regulatory element-binding protein-1
STAT3 Signal transducer and activator of transcription 3
Thr286 Threonine 286
TRAIL-Mediated apoptosis Tumor necrosis factor-related apoptosis-inducing ligand
uPA Urokinase-type plasminogen activator (uPA)
XIAP X-linked inhibitor of apoptosis protein
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