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Citation: Rahmani, A.H.;
Almatroudi, A.; Allemailem, K.S.;
Alwanian, W.M.; Alharbi, B.F.;
Alrumaihi, F.; Khan, A.A.;
Almatroodi, S.A. Myricetin: A
Significant Emphasis on Its
Anticancer Potential via the
Modulation of Inflammation and
Signal Transduction Pathways. Int. J.
Mol. Sci. 2023,24, 9665. https://
doi.org/10.3390/ijms24119665
Academic Editor: Estefanía
Burgos-Morón
Received: 19 April 2023
Revised: 27 May 2023
Accepted: 30 May 2023
Published: 2 June 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
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4.0/).
International Journal of
Molecular Sciences
Review
Myricetin: A Significant Emphasis on Its Anticancer Potential
via the Modulation of Inflammation and Signal
Transduction Pathways
Arshad Husain Rahmani 1, *, Ahmad Almatroudi 1, Khaled S. Allemailem 1, Wanian M. Alwanian 1,
Basmah F. Alharbi 2, Faris Alrumaihi 1, Amjad Ali Khan 2and Saleh A. Almatroodi 1
1Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University,
Buraydah 51452, Saudi Arabia
2Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University,
Buraydah 51452, Saudi Arabia
*Correspondence: ah.rahmani@qu.edu.sa
Abstract:
Cancer is a major public health concern worldwide and main burden of the healthcare
system. Regrettably, most of the currently used cancer treatment approaches such as targeted
therapy, chemotherapy, radiotherapy and surgery usually cause adverse complications including
hair loss, bone density loss, vomiting, anemia and other complications. However, to overcome these
limitations, there is an urgent need to search for the alternative anticancer drugs with better efficacy
as well as less adverse complications. Based on the scientific evidences, it is proven that naturally
occurring antioxidants present in medicinal plants or their bioactive compounds might constitute
a good therapeutic approach in diseases management including cancer. In this regard, myricetin,
a polyhydroxy flavonol found in a several types of plants and its role in diseases management as
anti-oxidant, anti-inflammatory and hepato-protective has been documented. Moreover, its role
in cancer prevention has been noticed through modulation of angiogenesis, inflammation, cell
cycle arrest and induction of apoptosis. Furthermore, myricetin plays a significant role in cancer
prevention through the inhibition of inflammatory markers such as inducible nitric oxide synthase
(iNOS) and cyclooxygenase-2 (Cox-2). Moreover, myricetin increases the chemotherapeutic potential
of other anticancer drugs through modulation of cell signaling molecules activity. This review
elaborates the information of myricetin role in cancer management through modulating of various
cell-signaling molecules based on
in vivo
and
in vitro
studies. In addition, synergistic effect with
currently used anticancer drugs and approaches to improve bioavailability are described. The
evidences collected in this review will help different researchers to comprehend the information
about its safety aspects, effective dose for different cancers and implication in clinical trials. Moreover,
different challenges need to be focused on engineering different nanoformulations of myricetin to
overcome the poor bioavailability, loading capacity, targeted delivery and premature release of this
compound. Furthermore, some more derivatives of myricetin need to be synthesized to check their
anticancer potential.
Keywords: myricetin; apoptosis; inflammation; cancer therapy; signal transduction pathways
1. Introduction
Cancer is a multifactorial disease and it has emerged as a significant disorder account-
able for a large number of deaths yearly worldwide [
1
]. More than 19.3 million new cancer
cases are diagnosed and reported recently, leading to almost 10 million deaths based on the
reported data [
2
]. In spite of the development of innumerable treatment approaches, cancer
remains a key cause of death worldwide [
3
,
4
]. The current mode treatment for cancer
patients is important, but these types of treatments cause some serious adverse effects such
as severe nausea and vomiting [5].
Int. J. Mol. Sci. 2023,24, 9665. https://doi.org/10.3390/ijms24119665 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2023,24, 9665 2 of 31
In this vista, approximately 50% of accepted cancer therapeutic agents are derived from
natural products as well as, secondarily; medicinal plant metabolites have established a
valuable perspective as a source of anti-cancer as well as chemo-preventive compounds [
6
].
Moreover, natural products have gathered growing consideration in cancer chemotherapy
as they are regarded as more biologically responsive and therefore more co-evolved with
their target sites as well as less toxic to normal cells [
7
]. Moreover, consumption of natural
products or their bioactive compounds is associated with a low risk of various pathogenesis
including cancer. Several studies have proven role of natural compound or their bioactive
compounds in the inhibition of pathogenesis including cancer through modulation of
various biological activities [8–11].
Various experimental studies exhibited that natural products presented inhibitory
potentials for cancer prevention via inhibiting proliferations, angiogenesis, cell migrations,
induction of apoptosis, and arresting the cell cycle [12–15]
Myricetin (3, 5, 7, 3
0
, 4
0
, 5
0
-hexahydroxyflavone), an important flavonoid and chiefly
found in the glycoside form (O-glycosides) in fruits, vegetables, berries, nuts, herbs, plants,
beverages and medicinal plants [16–22] (Figure 1).
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 2 of 32
proaches, cancer remains a key cause of death worldwide [3,4]. The current mode treat-
ment for cancer patients is important, but these types of treatments cause some serious
adverse effects such as severe nausea and vomiting [5].
In this vista, approximately 50% of accepted cancer therapeutic agents are derived
from natural products as well as, secondarily; medicinal plant metabolites have estab-
lished a valuable perspective as a source of anti-cancer as well as chemo-preventive com-
pounds [6]. Moreover, natural products have gathered growing consideration in cancer
chemotherapy as they are regarded as more biologically responsive and therefore more
co-evolved with their target sites as well as less toxic to normal cells [7]. Moreover, con-
sumption of natural products or their bioactive compounds is associated with a low risk
of various pathogenesis including cancer. Several studies have proven role of natural com-
pound or their bioactive compounds in the inhibition of pathogenesis including cancer
through modulation of various biological activities [8–11].
Various experimental studies exhibited that natural products presented inhibitory
potentials for cancer prevention via inhibiting proliferations, angiogenesis, cell migra-
tions, induction of apoptosis, and arresting the cell cycle [12–15]
Myricetin (3, 5, 7, 3′, 4′, 5′-hexahydroxyflavone), an important flavonoid and chiefly
found in the glycoside form (O-glycosides) in fruits, vegetables, berries, nuts, herbs,
plants, beverages and medicinal plants [16–22] (Figure 1).
Figure 1. Chemical structure of myricetin.
Previous finding supports the role of myricetin with antioxidant [23], anti-inflamma-
tory [24] hepato-protective [25] and anti-diabetic potential in diseases management [26].
Moreover, its role in various types of cancer has been explained through modulation of
various important cell-signaling molecules [27]. The recent studies demonstrate the po-
tential role of myricetin in cancer management through various hallmarks of cancer
through different molecular mechanisms employed by this flavonoid to mitigate cell pro-
liferation, angiogenesis, metastasis, and induction of apoptosis [28,29] and its role in inhi-
bition of other pathogenesis has been described [30].
This review summarizes the evidences of myricetin role in cancer management by
modulating different cell-signaling molecules based on in vitro and in vivo studies. In
addition, the synergistic effect with some anticancer drugs and approaches to enhance its
pharmacokinetics is discussed. The facts compiled in this review will help different health
professionals to comprehend the knowledge about its safety aspects, mechanism of action,
effective dose against cancers and implication in clinical trials.
Origin and Quantity of Myricetin in Different Plants
From the plants of Myricaceae, Comptonia peregrina (L.) Coult. and Morella cerifera (L.)
Small, first time myricetin was discovered [31,32]. The most common sources of myricetin
are fruits, vegetables, berries, nuts, as well as tea [33]. Rosa canina L. (rosa hip), Urtica dioica
L. (nettle), and Portulaca oleracea L. (purslane) plants contains myricetin concentration in
Figure 1. Chemical structure of myricetin.
Previous finding supports the role of myricetin with antioxidant [
23
], anti-inflammatory [
24
]
hepato-protective [
25
] and anti-diabetic potential in diseases management [
26
]. Moreover,
its role in various types of cancer has been explained through modulation of various im-
portant cell-signaling molecules [
27
]. The recent studies demonstrate the potential role of
myricetin in cancer management through various hallmarks of cancer through different
molecular mechanisms employed by this flavonoid to mitigate cell proliferation, angio-
genesis, metastasis, and induction of apoptosis [
28
,
29
] and its role in inhibition of other
pathogenesis has been described [30].
This review summarizes the evidences of myricetin role in cancer management by
modulating different cell-signaling molecules based on
in vitro
and
in vivo
studies. In
addition, the synergistic effect with some anticancer drugs and approaches to enhance its
pharmacokinetics is discussed. The facts compiled in this review will help different health
professionals to comprehend the knowledge about its safety aspects, mechanism of action,
effective dose against cancers and implication in clinical trials.
Origin and Quantity of Myricetin in Different Plants
From the plants of Myricaceae,
Comptonia peregrina (L.)
Coult. and
Morella cerifera (L.)
Small, first time myricetin was discovered [
31
,
32
]. The most common sources of myricetin
are fruits, vegetables, berries, nuts, as well as tea [
33
]. Rosa canina L. (rosa hip),
Urtica dioica L
.
(nettle), and Portulaca oleracea L. (purslane) plants contains myricetin concentration in the
range between 3 and 58 mg/kg [
20
]. Other sources of myricetin are bambara groundnut
(Vigna subterrania) with 1800 mg/g [
34
] and in the Lycium barbarum L. fruits, 57.2 mg of
myricetin/g [
35
]. Myricetin is also present in different vegetables and fruits as blueberry
(25 mg/kg) [
19
], Crowberry (44mg/kg) [
19
], green chilli (11.5 mg/kg) [
36
], red chilli
(29.5 mg/kg) [
36
], garlic (693 mg/kg) [
36
], guava (549.5 mg/kg) [
36
]. Other study reported
Int. J. Mol. Sci. 2023,24, 9665 3 of 31
that carrot (525.3 mg/kg), spinach (1660.9 mg/kg), turnip (457.0 mg/kg), cauliflower
(1586.9 mg/kg), and peas (146.2 mg/kg) contain myricetin [16].
2. Mechanism of Action of Myricetin in Cancer Prevention
Myricetin has been identified as having anti-cancer potential through modulation of a
variety of cell signalling molecules and pathways, including inflammation, apoptosis, cell
cycle, PI3K/Akt, angiogenesis, transcription factor/components, and also other compound
or molecules (Figure 2).
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 32
the range between 3 and 58 mg/kg [20]. Other sources of myricetin are bambara ground-
nut (Vigna subterrania) with 1800 mg/g [34] and in the Lycium barbarum L. fruits, 57.2 mg
of myricetin/g [35]. Myricetin is also present in different vegetables and fruits as blueberry
(25 mg/kg) [19], Crowberry (44mg/kg) [19], green chilli (11.5 mg/kg) [36], red chilli (29.5
mg/kg) [36], garlic (693 mg/kg) [36], guava (549.5 mg/kg) [36]. Other study reported that
carrot (525.3 mg/kg), spinach (1660.9 mg/kg), turnip (457.0 mg/kg), cauliflower (1586.9
mg/kg), and peas (146.2 mg/kg) contain myricetin [16].
2. Mechanism of Action of Myricetin in Cancer Prevention
Myricetin has been identified as having anti-cancer potential through modulation of
a variety of cell signalling molecules and pathways, including inflammation, apoptosis,
cell cycle, PI3K/Akt, angiogenesis, transcription factor/components, and also other com-
pound or molecules (Figure 2).
Figure 2. Possible mechanism of action of myricetin in cancer prevention.
Detailed possible mechanism of action of myricetin in cancer prevention are de-
scribed in the following sections.
2.1. Inflammation
It is widely understood that viral and bacterial infections, chronic inflammation, and
up to 25% of human cancers are linked [26]. Besides this, lipopolysaccharide (LPS), is a
commonly used compound to induce the inflammation in experimental animals. It is sig-
nificantly associated with chronic intestinal inflammation and initiates cancer progres-
sion. A crosstalk exists between LPS/TLR4 signal transduction pathway and different met-
abolic pathways including primary bile acid biosynthesis and secretion, renin-angiotensin
Figure 2. Possible mechanism of action of myricetin in cancer prevention.
Detailed possible mechanism of action of myricetin in cancer prevention are described
in the following sections.
2.1. Inflammation
It is widely understood that viral and bacterial infections, chronic inflammation,
and up to 25% of human cancers are linked [
26
]. Besides this, lipopolysaccharide (LPS),
is a commonly used compound to induce the inflammation in experimental animals.
It is significantly associated with chronic intestinal inflammation and initiates cancer
progression. A crosstalk exists between LPS/TLR4 signal transduction pathway and
different metabolic pathways including primary bile acid biosynthesis and secretion, renin-
angiotensin system, arachidonic acid pathways and glutathione metabolism, important in
driving chronic intestinal inflammation and intestinal carcinogenesis [37].
The hallmark in the commencement and proliferation of cancer is also characterized
by inflammation associated with cancer [
38
]. Furthermore, the fact that significant pro-
inflammatory transcription factors like nuclear factor-
κ
B (NF-
κ
B) and signal transducers
and activators of transcription 3 can be induced via a multitude of these dynamic cancer
risk factors clearly illustrates the crucial relationship between chronic inflammation and
cancer [39]. The chronic inflammatory microenvironment is predominated by build-up of
Int. J. Mol. Sci. 2023,24, 9665 4 of 31
macrophages. The macrophages, in combination with other leukocytes, produce excessive
reactive oxygen species (ROS) and reactive nitrogen species (RNS) to fight infection [
40
].
However, a continuous tissue damage and cellular proliferation leads to the persistence
of these infection-fighting agents, which is deleterious. Mutagenic agents are usually pro-
duced during this phenomenon. The different mutagenic agents include peroxynitrite,
which cause DNA mutation in proliferating epithelial and stroma cells. Macrophages
and T-lymphocytes may release tumor necrosis factor-
α
(TNF-
α
) and macrophage mi-
gration inhibitory factor to exacerbate DNA damage [
41
]. These overall events lead to
cancer development.
Moreover, the chronic inflammation can lead to cancer in target organs as well
as several tissues via multiple pathways [
42
]. Various natural compounds show anti-
inflammatory potential via inhibiting the production of inflammatory mediators or related
signalling molecules [43–48].
A recent study reported that myricetin significantly inhibited cytokine-initiated mi-
gration and invasion of cholangiocarcinoma cells. Moreover, the cytokine-initiated up-
regulation of metastasis and inflammatory-linked genes, which are downstream genes
of STAT3 together with the inducible nitric oxide synthase (iNOS), intercellular adhesion
molecule-1 (ICAM-1), cyclo-oxygenase 2 (Cox-2) and matrix metalloproteinase-9 (MMP-9)
were meaningfully stopped by the treatment of myricetin [
49
] (Table 1). Myricetin inhibited
the occurrence of colorectal tumorigenesis and decrease the size of colorectal polyps [
50
].
Besides, myricetin could reduce the amount of colonic inflammation and colorectal tu-
morigenesis. Additional finding exhibited that myricetin powerfully decrease the levels
of the inflammatory factors in the colonic tissues. Myricetin holds the biological activities
of the chemoprevention of colonic chronic inflammation, as well as inflammation-driven
tumorigenesis [
50
]. Myricetin played role in the inhibition of NLRP3 inflammasome assem-
bly through promotion of ROS-independent ubiquitination of NLRP3 as well as decrease
of ROS-dependent ubiquitination of apoptosis-associated speck-like protein comprising
a CARD (ASC), which disturbs the interaction between NLRP3 and ASC and prevents
the ASC oligomerization [
51
]. The effects of myricetin on blood concentrations of PGE2
and interleukin-6 (IL-6) as well as pro-inflammatory cytokines (MCP-1, TNF-
α
, IL-1
β
, and
IL-6) in adenomatous polyps were investigated. Result revealed that both IL-1
β
precursor
as well as mature IL-1
β
were strongly prevented in small intestinal and colonic polyps.
Furthermore, it demonstrated that myricetin decrease the levels of TNF-
α
by 89.4% and
91.9%, IL-6 by 76.6% and 89.2% and MCP-1 by 77.2% and 83.3% in small intestinal and
colonic polyps, correspondingly [
52
]. Inflammatory cytokine secretions were meaningfully
inhibited by myricetin pretreatment. These finding enrich the full bioactivities of myricetin
and demonstrate that myricetin has potential anti-inflammatory property [53].
2.2. Apoptosis
Apoptosis is defined as a type of controlled cell death initiaed by a programmed
cascade of molecular steps. However, when the physiological process tended to be altered,
several pathological transformations occur to develop malignancy [
54
]. Thus, it was
confirmed that controlling and induction of apoptosis are possible ways in the treatment of
cancer [
55
,
56
]. By causing cancer cells to undergo apoptosis, natural compounds have a
documented role in cancer prevention. Furthermore, there were apoptotic bodies in the cell
and vesicles in the cell membrane. The percentage of apoptotic cells was 28.5 and 67.4% in
the 50 and 100
µ
mol/L myricetin-exposed groups, respectively. Flow cytometry exhibited
similar findings, with the apoptotic rate being positively correlated with the concentration
of myricetin (50 and 100
µ
mol/L). Besides, myricetin (25, 50 and 100
µ
mol/L) reduced
the ratio of Bcl-2/Bax and induced apoptosis in a dose-dependent manner [
57
] (Table 1).
A recent study reported that apoptotic bodies in the gastric cancer cells were exposed
with myricetin. The number of apoptotic bodies significantly increased as myricetin
concentration increased, primarily by 2.0% in the control group, 6.0% in the myricetin
(15
µ
M) treatment group, and 17.7% in the myricetin (25
µ
M) treatment group. Moreover,
Int. J. Mol. Sci. 2023,24, 9665 5 of 31
expression of anti-apoptosis protein decreased and pro-apoptosis proteins increased in the
myricetin treatment groups when compared to control group [
58
] (Table 1). The apoptosis
in myricetin-treated cells was examined to provide an explanation for the cytotoxicity
associated with myricetin in ovarian cancer cells. Ovarian cancer cells receiving myricetin
treatment showed signs of apoptosis induction. Besides, myricetin (25
µ
M) treatment
caused the apoptotic signal in ovarian cancer cell to increase by about 2.5 times, while
the same treatment caused the apoptotic signal in other ovarian cancer cells (OVCAR3) to
increase by about 4-fold when compared to untreated cells. The consequences propose that
apoptosis is participated in myricetin-initiated cytotoxicity in certain ovarian cancer cells.
Furthermore, pro-apoptotic protein was suggestively increased, and the expression of the
anti-apoptotic protein decreased in myricetin-treated ovarian cancer cells [
59
]. Another
important study result based on flow cytometry analysis demonstrated that myricetin (0, 50,
100
µ
mol/L) led to apoptosis in prostate cancer cells. In addition, western blotting result
presented that expression levels of the apoptosis-associated proteins cleaved caspase-3 and
cleaved caspase-9 were both enhanced in DU145 and PC3 cells after treatment of myricetin
(0, 50, 100 µmol/L) [60] (Table 1).
2.3. Cell Cycle
Regulation of cell cycle is an important step in cancer prevention and treatment.
Natural compounds have proven role in cancer prevention through cell cycle arrest. The
question of whether arrest of cell cycle in cancer cells is related to myricetin treatment was
explored in an investigation based on hepatocellular carcinoma (HCC). Liver cancer cell
(HepG2 as well as Hep3B) treated with myricetin (0, 25, 50
µ
M) Showed a clear reduction
in cell number in the G0/G1 stage, while the cell cycle was observed to be arrested at the
G2/M stage. The proliferative nuclei were intensely declined in a concentration-dependent
way when cells were treated in myricetin. These outcomes designated that myricetin
suppressed cancer cell proliferation, most probably by stopping cell cycle at the G2/M
phase [61] (Table 1).
Anticancer potential of the myricetin in A549 lung cancer cells was examined. Among
numerous doses of myricetin, 73
µ
g/mL was more effective to inhibit the cancer cell growth.
It also indorsed sub-G1 phase aggregation of cells as well as an equivalent reduction in
the fraction of cells entering the S and subsequent phase which designates apoptotic cell
death. Myricetin generated huge free radicals and, changed the potential of mitochondrial
membrane in A549 cells. These results advised that myricetin shows cytotoxic potential
via arresting the progression of cell cycle and ROS-dependent mitochondria-mediated
mortality in cancer A549 lung cancer cells [62] (Table 1).
When thyroid cancer cells were in the sub-G1 stage, myricetin caused a concentration-
dependent arrest of growth. In comparison to untreated control cells, the proportion of
cells in the sub-G1 stage was larger in cells subjected to myricetin. In contrast, cells exposed
to myricetin (100
µ
M) had a percentage of S phase cells of 17.70
±
7.66% and untreated cells
had a percentage of 10.42
±
2.95%. According to this finding, myricetin’s ability to stop
cells in the sub-G1 phase is one of the ways it killed cancer cells [
63
]. Flow cytometry-based
finding revealed that myricetin caused cell cycle arrest and apoptosis in gastric cancer cells.
Flow cytometry based study was performed to evaluate the effect of myricetin on the cell
cycle in gastric cancer cells. As compared with control groups, the 20 and 40
µ
mol/L groups
showed a lower percentage of cells in S-phase and a higher percentage in G2/M-phase.
Compared with the 20 mol/L group, the 40
µ
mol/L group had a lower percentage of
S-phase cells and a higher percentage of G2/M-phase cells. Compared with the control
groups, cyclin B1, cyclin D1, CDK1, and CDC25C were meaningfully decreased in the
20 and 40 mol/L groups, with a higher decrease in the 40 mol/L group [64].
2.4. Angiogenesis
Angiogenesis shows a vital role in the development and progression in various
pathogenesis [65–67].
Natural products inhibit cancer development and progression through
Int. J. Mol. Sci. 2023,24, 9665 6 of 31
its anti-angiogenic activity. The potential role of myricetin on ultraviolet B (UVB)-caused
vascular endothelial growth factor (VEGF) expression in SKH-1 hairless mouse skin was
explored. Result reported that myricetin treatment significantly inhibited UVB-induced
expression of VEGF [
68
]. Inhibition of VEGF levels by myricetin (5 and 20
µ
M) therapy
resulted in VEGF levels of 74.4 and 51.9% in A2780/CP70 cells and 74.9 and 46.9% in
OVCAR-3 cells. It was investigated
in vitro
whether the culture medium of ovarian cancer
cells exposed to various concentrations of galangin and myricetin caused tube formation
through HUVEC cells. The findings showed that HUVEC cells formed a well-solidified
network
in vitro
and
in vitro
angiogenesis was promoted by culture media that was condi-
tioned by these cancer cells. After galangin and myricetin treatment, HUVEC networks
were shortened significantly. Moreover, galangin and myricetin treatment showed sub-
stantial decrease in tube length. VEGF levels were 74.4 and 51.9% in A2780/CP70 cell
and 74.9 and 46.9% in OVCAR-3 cell inhibited by 5 and 20
µ
M myricetin treatment [
69
]
(Table 1). Another choriocarcinoma study found that myricetin intervention lowered the
pro-angiogenic and invasive activity of malignant JAR as well as JEG-3 trophoblast cells
via the phosphatidyl inositol-3-kinase (PI3K)/AKT and mitogen activating protein kinase
(MAPK) signalling cascades. Further, cell invasion was suppressed approximately 90% by
20 mM myricetin in both JAR and JEG-3 cells. In conditioned medium from JAR cells, the
concentration of VEGFA was decrease 40% in response to myricetin [70].
2.5. PI3K/Akt Pathways
Alteration of the PI3K/AKT/mTOR signaling pathway by either the mutation or
amplification of genes participated in the PI3K pathway, overactivation of RTKs or loss
of the tumor suppressor PTEN, has been noticed in several cancer cells, causal to tumor
progression as well as metastasis [
71
–
74
]. Natural substances have demonstrated a role
in the prevention of cancer by inhibiting the PI3K/AKT signaling cascade. Myricetin
therapy demonstrated a contribution to decreasing colon cancer cell line proliferation.
Additionally, myricetin (50 and 100
µ
mol/L) induced cell apoptosis and autophagy by
inhibiting PI3K/Akt/mTOR signalling pathway [
57
] (Table 1). Furthermore, myricetin
inhibits the PI3K/Akt/mTOR pathway, commencing autophagy and apoptosis, which
lowers the survival rate of gastric cancer cells. The expression of p-PI3K, p-Akt and p-
mTOR decreased in a concentration-dependent manner in the myricetin (15 and 25
µ
M)
treatment groups as compared to that in the control group. As a result, myricetin appears
to inhibit the PI3K/Akt/mTOR pathway in gastric cancer cells, which prevents the growth
of cancer cells and promotes cell-protective autophagy as well as
in vivo
and
in vitro
apop-
tosis [
44
]. Myricetin reduced the levels of phosphorylated p-Akt, p-MAPK, and
p-P38 [75]
and myricetin induces apoptosis through ROS induction and inhibits cell migration, tube
formation, and PI3K/Akt/mTOR signaling in human umbilical vascular endothelial cells.
Myricetin (0.25, 0.5, 1.0
µ
M) attenuated the phosphorylation of both PI3K and PDK1 in
a concentration-dependent manner [
76
]. Another study based on triple-negative breast
cancer cells reported that myricetin modulated pro-angiogenic, cell cycle, and invasion
effects through the PI3K/Protein kinase B (PKB/also known as AKT) and MAPK signaling
pathways [77].
2.6. Signal Transducer and Activator of Transcription 3 (STAT3)
The role of myricetin on inflammatory cytokine-initiated STAT3 pathway activation
of cholangiocarcinoma cells was examined. The results demonstrated that the cytokine
mixture such as IL-6 + IFN-
γ
plus TNF-
α
caused STAT3 pathway initiation, clearly by an
enhancement phosphorylation of STAT3. Exposure of cancer cells with myricetin showed
role in the suppression of STAT3 phosphorylation in a dose-dependent way [
49
] (Table 1).
A study using hepatocellular carcinoma (HCC) cells was carried out to determine if what
myricetin causes autophagy and cell cycle arrest in HCC cells by modulating the MARCH1-
regulated p38 MAPK/Stat3 signalling pathway. Myricetin (0.25, 0.5, 1.0
µ
M) treatment has
been shown to restrict the expression of p-Stat3 and p-p38 MAPK in cancer cells [61].
Int. J. Mol. Sci. 2023,24, 9665 7 of 31
2.7. Autophagy
Autophagy has dual effect on cancers, which may protect cancer cells from extreme
nutrient conditions, whereas it also causes destruction of energy homeostasis as well as
kill cancer cells [
78
]. Natural compounds or their bioactive ingredient play role in the
modulation of autophagy. Vacuoles were seen in the myricetin-exposed gastric cancer
cells, in the myricetin treatment groups showed higher number of vacuoles. Furthermore,
autolysosomes were recognized in the gastric cancer cells. With an increment in myricetin
concentration, the amount of positively stained cells gradually enhanced, while in the
control group, very few positively stained cells were seen.
The myricetin treatment groups displayed an important increase of the ratio of LC3-
II/LC3-I as well as concentrations of protein named as beclin 1 when compared to control
group [
58
]. Whether myricetin caused autopaghy in liver cancer HCC cells was examined.
Western blotting was used to analyse the levels of p62, LC3-I, and LC3-II in SMMC-7721
and Hep3B cells. It was observed that there was a significant improvement in the ratio of
LC3-II/LC3-I and a dose-dependent decrease in the protein level of p62. To further verify
this finding, Human Hepatocellular carcinoma (HCC) cell lines SMMC-7721 and Hep3B
cells had been transfected with GFP-LC3 plasmids and were strongly expressing GFP-LC3
were exposed to myricetin at various concentrations (0, 100, and 200
µ
M). As a result, it was
observed that there was an intentional increase in the percentage of cells forming GFP-LC3
puncta in a dose-dependent manner (0, 100, and 200
µ
M) [
79
] (Table 1). An important study
was performed to evaluate whether myricetin caused autophagy in HepG2 cells. After
treatment with myricetin (0, 20, 50
µ
M) for 24 h, GFP-LC3 changed from the dispersion
state to a punctuate state, indicating that myricetin can convert the soluble form of LC3-I to
the lipidated and autophagosome-associated form LC3-II, therefore promoting autophagy.
Moreover, myricetin treatment enhanced the LC3-II level in a dose-dependent way. In the
meantime, the expression of essential autophagic protein PI3K III was increased as well,
along with the reduced expression of anti-apoptotic protein [80].
Table 1. Mechanism of action of myricetin in cancer prevention.
Pathways Cell Line Cancer Mechanism/Outcomes Refs.
Inflammation KKU-100
Cholangiocarcinoma
Myricetin suggestively inhibited cytokine-initiated
migration and invasion of cancer cells. The
cytokine-initiated upregulation of metastasis and
inflammatory-linked genes were meaningfully
stopped by the treatment of myricetin
[49]
Apoptosis
HCT116 and
SW620 Colorectal cancer
Myricetin decreased the Bcl-2/Bax ratio and caused
apoptosis in a concentration-dependent manner.
Cancer cells exposed with myricetin showed
apoptotic cells became rounder and smaller
[57]
AGS Gastric cancer
As compared to 28.93% in the control group, the
percentage of apoptotic cells were significantly
increased to 39.94% in the group treated
with myricetin.
[58]
A2780 and
OVCAR3 Ovarian cancer
Myricetin treatment was seen to induce apoptosis in
cancer cells. Pro-apoptotic protein was suggestively
increased, and the expression of the anti-apoptotic
protein decreased in myricetin-treated group
[59]
DU145 and PC3 Prostate Cancer
Myricetin pointedly brought apoptosis. Constantly,
expression levels of the apoptosis-associated proteins
cleaved caspase-3 as well as cleaved caspase-9 after
treatment of myricetin
[60]
Int. J. Mol. Sci. 2023,24, 9665 8 of 31
Table 1. Cont.
Pathways Cell Line Cancer Mechanism/Outcomes Refs.
Cell cycle
Hep3B and
HepG2
Hepatocellular cell
carcinoma
Cell cycle arrest in HCC cells due to myricetin
occurred at the G2/M stage. Myricetin inhibited the
proliferation of cancer cells, presumably through
blocking the cell cycle just at G2/M stage.
[61]
A549 Lung cancer
Myricetin induced sub-G1 phase aggregation of cells
and reduce in the fraction of cells incoming the S as
well as subsequent phase
[62]
SNU-80 and
HATC cell
Human Anaplastic
Thyroid Cancer
The proportion of cells present in the sub-G1 stage
and S stage was higher in those cells that were
exposed with myricetin as compared to untreated
control cells
[63]
GC HGC-27 and
SGC7901 cells Gastric cancer
Myricetin influenced apoptosis as well as cell cycle
arrest of gastric cancer cells via regulating
related proteins
[64]
Angiogenesis
A2780/CP70 and
OVCAR-3 cells Ovarian cancer
Vascular endothelial growth factor (VEGF), a
mediator of angiogenesis, was inhibited by myricetin
and galangin in cancer cells.
[69]
JAR and JEG-3 Choriocarcinoma
Pro-angiogenic and invasive activity of malignant
JAR as well as JEG-3 trophoblast cells were reduced
by treatment of myricetin
[70]
PI3K/Akt
HT-29, HCT116,
SW480 and
SW620
Colorectal cancer
Myricetin caused cell apoptosis as well as autophagy
through preventing PI3K/Akt/mTOR
signalling pathway
[57]
AGS Gastric cancer
Myricetin inhibits the PI3K/Akt/mTOR pathway,
which lowers the rate of survival of gastric
cancer cells.
[76]
STAT3 KKU-100
Cholangiocarcinoma
Exposure of cancer cells with myricetin showed role
in the suppression of STAT3 phosphorylation in a
dose-dependent way
[49]
Autophagy
Hep3B and
HepG2
Hepatocellular
carcinoma
Intervention with myricetin decreases the expression
of p-Stat3 and p-p38 MAPK in cancer cells. [61]
AGS Gastric cancer
Vacuoles were seen in the myricetin-exposed gastric
cancer cells, in the myricetin treatment groups
showed higher number of vacuoles.
[58]
SMMC-7721 and
Hep3B cells
Hepatocellular
carcinoma
LC3-II/LC3-I ratio was significantly increased.
However, the protein level of p62 was clearly
lowered in a concentration-dependent way.
[79]
3. Myricetin: Potential Role in Different Types of Cancer
Various experimental studies exhibited that natural products presented inhibitory
potentials for cancer prevention via inhibiting proliferations, angiogenesis, cell migrations,
induction of apoptosis, and arresting the cell cycle [12–15] (Figure 3).
Role of myricetin in different types of cancers are described as (Table 2).
3.1. Prostate Cancer
Prostate cancer is the second most frequent malignancy (after lung cancer) in men
worldwide, counting 1,276,106 new cases and causing 358,989 deaths [
81
]. Myricetin has
established its role in prostate cancer growth inhibition through modulation of various
cell-signalling pathways. Flow cytometry analysis exhibited that myricetin meaningfully
induced apoptosis in prostate cancer cells. In the meantime, lower apoptosis rates were
noticed in RWPE-1 cells, in accordance with the cytotoxicity assays. Consistently, Western
Int. J. Mol. Sci. 2023,24, 9665 9 of 31
Blotting analysis exhibited that the expression levels of the apoptosis-related proteins
cleaved caspase-3 and cleaved caspase-9 were both upregulated in PC3 and DU145 cells
after myricetin treatment. Also, myricetin inhibited the phosphorylation of ERK1/2 and
AKT in PC3 and DU145 cells [
60
]. A recent and important study reported that myricetin
is a potent
α
-ketoglutarate-type inhibitor that significantly reduces the proliferation of
both androgen-dependent and androgen-independent CRPC by inhibiting demethylation
activity via KDM4s (C4-2B and CWR22Rv1). Enzalutamide and myricetin have been found
to have a synergistic cytotoxic effect on C4-2B. Additionally, in the C4-2B xenograft model,
PLGA-myricetin, enzalutamide, and the combination treatment showed significantly better
antitumor potential than the control group. Additionally, the co-administration appeared
to slow tumor growth compared to enzalutamide or myricetin treatment alone [82].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 9 of 32
STAT3 phosphorylation in a dose-de-
pendent way
Autophagy
Hep3B and
HepG2
Hepatocellular carci-
noma
Intervention with myricetin decreases
the expression of p-Stat3 and p-p38
MAPK in cancer cells.
[61]
AGS Gastric cancer
Vacuoles were seen in the myricetin-ex-
posed gastric cancer cells, in the myrice-
tin treatment groups showed higher
number of vacuoles.
[58]
SMMC-7721 and
Hep3B cells
Hepatocellular carci-
noma
LC3-II/LC3-I ratio was significantly in-
creased. However, the protein level of
p62 was clearly lowered in a concentra-
tion-dependent way.
[79]
3. Myricetin: Potential Role in Different Types of Cancer
Various experimental studies exhibited that natural products presented inhibitory
potentials for cancer prevention via inhibiting proliferations, angiogenesis, cell migra-
tions, induction of apoptosis, and arresting the cell cycle [12–15] (Figure 3).
Figure 3. Role of myricetin in different of types of cancers through modulation of cell signalling
molecules.
Role of myricetin in different types of cancers are described as (Table 2).
3.1. Prostate Cancer
Prostate cancer is the second most frequent malignancy (after lung cancer) in men
worldwide, counting 1,276,106 new cases and causing 358,989 deaths [81]. Myricetin has
established its role in prostate cancer growth inhibition through modulation of various
Figure 3.
Role of myricetin in different of types of cancers through modulation of cell sig-
nalling molecules.
3.2. Colon Cancer
The third most frequent type of cancer is colorectal cancer (CRC) and it is the second
foremost cause of cancer death globally [
83
,
84
]. Myricetin has proven role in CRC manage-
ment through modulation of various cell-signalling pathways. Death of human colon cancer
cells (HCT-15) was induced after the treatment of myricetin in a dose-dependent means.
When compared to controls, 70% decrease in cell viability on human colon cancer cells was
noted with the treatment of myricetin (100
µ
M). To examine apoptotic cell death and DNA
damage of colon cancer cells, different concentration of myricetin was used to treat cancer
cells. Myricetin (100
µ
M) treatment of HCT-15 induced substantial nuclear rounding as
well as shrinkage of human colon cancer cells as compared to controls. Moreover, effect
of myricetin on apoptosis was observed as myricetin enhanced the ratio of BAX/BCL2
as well as BAK expression. However, the expression of procaspase-3 as well as caspase-9
were hardly changed in human colon cancer (HCT-15) cells following myricetin (100
µ
M)
treatment [
85
]. The anti-cancer effects induced by myricetin treatment in colon cancer
HCT-15 cells was evaluated. Based on overall findings, it was proposed that myricetin
causes induction of apoptosis in human colon cancer cells selectively via enhancing the
expression of NDPK as well as other caspase-regulated apoptosis proteins [
86
]. The toxic
Int. J. Mol. Sci. 2023,24, 9665 10 of 31
role of myricetin loaded in solid lipid nanoparticles (MCN-SLNs) on the human CRC cells
(HT-29) were examined. Result revealed that myricetin loaded in solid lipid nanoparticles
could reduce colony numbers as well as survival of the HT-29 cells. The apoptosis index
of myricetin loaded in solid lipid nanoparticles-treated cells meaningfully enhanced as
compared to the free myricetin. The expression of AIF and Bax were elevated whereas Bcl-2
expression was reduced in myricetin loaded in solid lipid nanoparticles treatment [
87
].
Another study result revealed that proliferation of four types of colon cancer cell lines was
inhibited by myricetin. Moreover, PI3K/Akt/mTOR signalling pathway was inhibited and
induction of apoptosis and autophagy was observed after myricetin treatment. Moreover,
colon cancer cells exposed to myricetin were induced to undergo apoptosis by the inhibition
of autophagy with 3-methyladenine [57].
3.3. Liver Cancer
Hepatocellular carcinoma (HCC), the leading variety of liver cancers, accounts the
sixth predominant and fourth leading cause of cancer death worldwide [
81
]. Natural
compound including myricetin has recognized role in liver cancer prevention and treat-
ment via modulation of various cell-signalling molecules. To explore the mechanisms
underlying myricetin preventing cell growth, proliferation as well as apoptosis of HCC
cells treated with myricetin was compared. Result confirmed that proliferation of Huh-7
and HepG2 cells was inhibited by myricetin treatment. Additionally, HepG2 cells treated
with myricetin showed significant increased apoptosis rate as compared to control cells and
similar pattern was noticed for Huh-7 cells. Besides, myricetin induced Huh-7 and HepG2
cell apoptosis in a time-dependent way. In myricetin-treated HCC cells, cleaved caspase3
levels meaningly increased. Furthermore, other parameters were also checked as myricetin
inhibited YAP expression via encouraging its phosphorylation as well as subsequent degra-
dation. Myricetin prevented YAP expression by stimulating LATS1/2kinase activation [
88
].
To examine the cytotoxic effect of myricetin, HCC cell lines, Hep3B and SMMC-7721 of
human HCC cells was used and treated with different concentrations of myricetin. The
results demonstrated that myricetin considerably inhibited the proliferation of HCC cells
in a concentration- and time-dependent manner. The cytotoxic activity of myricetin was
investigated to determine whether it is cancer-selective. The cell line HL-7702, a human
normal hepatocyte cell line, was treated with myricetin, and the IC50 values were 252.2
µ
M
(24 h) and 163.9
µ
M (48 h), which were significantly higher than those of SMMC-7721 and
Hep3B cells. Additionally, it appeared that myricetin’s inhibitory activity on HL-7702 cells
was relatively weak compared to that of SMMC-7721 as well as Hep3B cells [79].
The role of myricetin on the migration as well as invasion of HCC MHCC97H cells
was investigated. It was designated that myricetin reduced the MHCC97H cells viability
in a concentration and time dependent way, and migration and invasion of MHCC97H
cells was inhibited. As the dose of myricetin increased, lamellipodia and filopodia in cells
weakened as well as cells were arranged more nearly. Moreover, myricetin decreased
N-cadherin and enhanced E-cadherin expression. Together, the results of the current study
establish that myricetin may inhibit the HCC MHCC97H cells migration and invasion by
inhibiting the EMT process [89].
Other findings demonstrated that myricetin treatment clearly reduced the viability
of HCC cells in a dose-dependent manner. Different doses of myricetin were applied
to HCC cells to test whether MARCH1 is involved in the anti-HCC effect. Both Hep3B
and HepG2 cells showed a reduction in MARCH1 expression. Additionally, myricetin
treatment significantly decreased the number of living HCC cells, especially at the 50
µ
M
concentration. Results also showed that MARCH1 overexpression partially prevented
MARCH1 downregulation brought on by myricetin and partially offset the antitumor effect
of myricetin. The mRNA level of MARCH1 was interestingly increased by myricetin in
Hep3B cells, but significantly decreased in HepG2 cells [61].
Int. J. Mol. Sci. 2023,24, 9665 11 of 31
3.4. Gastric Cancer
The MTT assay was performed to investigate the effect of myricetin on the cell viability
of AGS gastric cancer cells. The viability of cancer cells treated with different concentrations
of myricetin was 95.8% for 5
µ
M, 90.3% for 10
µ
M, 80.6% for 15
µ
M, and 64.6%, 52.7%, and
36.3% for 20
µ
M, 25
µ
M, and 30
µ
M, respectively. This showed that as the doses of myricetin
increased, the viability of gastric cancer cells gradually decreased in comparison to the
control group. Apoptosis and autophagy were induced as a result of myricetin inhibition of
the PI3K/Akt/mTOR pathway, which also reduced the survival rate of gastric cancer cells.
In vivo
, a related study was conducted and tumour growth was suppressed [
58
]. Another
study based on flow cytometry analysis exhibited that myricetin induces apoptosis and cell
cycle arrest in gastric cancer cells. Moreover, western blotting designated that myricetin
influenced apoptosis and cell cycle arrest of gastric cancer cells by regulating associated
proteins. SPR analysis presented strong binding affinity of ribosomal S6 kinase 2 (RSK2)
and myricetin. Myricetin bound to RSK2, leading to increased expression of Mad1, and
contributed to inhibition of HGC-27 and SGC7901 cell proliferation [64].
3.5. Pancreatic Cancer
The potential impact of myricetin on pancreatic cancer cells’ viability was assessed,
and it was observed that treatment with myricetin significantly decrease cell viability in
used pancreatic cancer cells (Panc-1, MIA PaCa-2, and S2-013) in a dose-dependent way,
whereas on normal pancreatic ductal cells, mild effect was seen. Additionally, the role
of caspase-3 and caspase-9 in myricetin-induced cell death was investigated. Myricetin-
containing culture medium was used to treat S2-013 and MIA PaCa-2 for 6 h, which resulted
in a significant increase in caspase-3 and -9 activity compared to the control. Additionally,
a dose-dependent enhancement of Annexin V positive cells was produced after all tested
pancreatic cancer cells were exposed to myricetin for 24 h. This finding supports the notion
that apoptosis facilitates myricetin-induced cell death in pancreatic cancer cells. To examine
the effects of myricetin on pancreatic cancer growth and local regional spread/metastasis
in vivo
, it was tested the efficacy of this compound on an orthotopic model of pancreatic
cancer.
In vivo
, treatment of orthotopic pancreatic tumors with myricetin showed tumor
regression and decreased metastatic spread [90].
3.6. Bile Duct Cancer
Biliary tract cancer is a diverse group of extremely aggressive cancers together with
perihilar/intrahepatic/distal cholangiocarcinoma, gallbladder cancer, as well as ampullary
cancer [
91
]. Natural compound including myricetin has documented role in bile duct cancer
prevention and treatment via modulation of various cell signalling molecules. A recent
study based on cholangiocarcinoma was performed and finding revealed migratory capabil-
ity initiated by cytokine of cholangiocarcinoma cells exposed with myricetin was evidently
stopped in a dose-dependent way [
49
]. Similarly, myricetin could meaningfully suppress
cytokine-induced invasion of cholangiocarcinoma cell. Furthermore, cytokine treatment
remarkably enhanced the expression of ICAM-1and MMP-9. Treatment with myricetin
meaningfully suppressed cytokine-mediated enhancement of these two genes. Moreover,
myricetin also abolished cytokine-caused expression of COX-2 and iNOS, which are the
critical molecules, participated in inflammatory as well as carcinogenesis processes [49].
3.7. Esophageal Cancer
Myricetin’s potential impact on the chemosensitivity of tumor cells was investigated.
It was found that treating esophageal cancer (EC9706) cells with different concentrations
of 5-fluorouracil (5-FU) on its own could have a preventive effect on clonogenic survival.
However, the surviving fraction significantly dropped when mixed with various myricetin
doses. The phases distribution of cell cycle indicated that both 5-FU and myricetin could
increase the percentage of EC9706 cells in G0/G1 phase and prevent cells entering into the
S phase. Additionally, myricetin or 5-FU treatment of esophageal cancer (EC9706) cells
Int. J. Mol. Sci. 2023,24, 9665 12 of 31
resulted in a notable rise in the G0/G1 stage, which was accompanied by a drop in the S
stage. In contrast to myricetin alone (62.1%) or 5-FU alone (68.8%), the percentage of cells in
the G0/G1 phase increased significantly when combined with 5-FU to 85.9%. These findings
suggest that myricetin may increase 5-FU chemosensitivity on cell cycle arrest in the G0/G1
phase, retard the start of the cell cycle, and inhibit EC9706 cells proliferation. An esophageal
cancer EC9706 cell xenograft mice model was used to determine chemosensitizing effect of
myricetin
in vivo
. It was found that myricetin-alone group showed less inhibitory effect
on tumor growth, compared with tumors treated with 5-FU only. Though, a significant
slower down in tumor growth occurred for mice treated with 5-FU combination with
myricetin [
92
]. Proliferation, apoptosis, and invasion of the esophageal carcinoma cell lines
(EC9706 and KYSE30) were examined in relation to the effects of myricetin. Myricetin
stopped proliferation as well as invasion and caused the induction of apoptosis of the
esophageal carcinoma cell lines. Additionally, it was discovered that myricetin binds RSK2
through the NH2-terminal kinase domain. Further, myricetin demonstrated induction of
cell apoptosis through Bad and it was found to suppress the proliferation of KYSE30 and
EC9706 cells through Mad1. Through RSK2, myricetin inhibits KYSE30 and EC9706 cells’
proliferative and invasive potential and triggers apoptosis. These findings provide novel
insight into the potential of myricetin as a preventive and therapeutic agent for esophageal
carcinoma [93].
3.8. Ovarian Cancer
Ovarian cancer is one of the utmost common causes of death of cancer among women
worldwide and the second most common reason of death from gynecological cancers [
81
].
CCK-8 cell viability/cytotoxicity assays showed that the optimal concentration range for
Myricetin inhibition of SKOV3 proliferation was 1
×
10
−5
–1
×
10
−4
M for 24 h. At these
concentrations, myricetin showed inhibitory role on SKOV-3 cells in a dose-dependent
means while not toxic to IOSE-80, non-tumor cells. SKOV3 cells treated with myricetin
looked smaller, with a reduced cell, as well as high-rate cell death. Furthermore, ROS
levels in these cancer cells were meaningfully decreased by the treatment of myricetin at
10, 20 and 40
µ
M in a dose dependent way and intracellular MDA was reduced whereas
SOD levels enhanced. Comparative to controls, exposure with myricetin meaningfully
decreased the number of SKOV3 cells migrating downward as well as invading matrigel
in a dose-dependent means [
94
]. The involvement of apoptosis in myricetin-exposed
cells was investigated in order to clarify the basic mechanisms by which myricetin causes
cytotoxicity in ovarian cancer cells. It was observed that myricetin treatment promoted
apoptosis in OVCAR3 and A2780 cells. Compared to untreated cells, in A2780 cells treated
with 25
µ
M myricetin cells showed an approximately 2.5-fold increase in the apoptotic
signal, whereas OVCAR3 cells showed an approximately 4-fold increase. The outcomes
advocate that apoptosis is participated in myricetin-caused cytotoxicity in ovarian cancer
cells. Additionally, it was also demonstrated that the expression of the anti-apoptotic
protein Bcl-2 was decreased and, the expression of a pro-apoptotic protein called as BAX
(B-cell lymphoma-2 -associated X-protein) was noticeably elevated in myricetin-treated
ovarian cancer cells in the comparison of untreated cells [
59
]. Viability of SKOV3 cells
was inhibited by the administration of myricetin in a concentration-dependent means.
Myricetin enhanced the protein levels of active caspase 3 and induced nuclear chromatin
condensation and fragmentation. Furthermore, myricetin upregulated ER stress-linked
proteins, C/EBP homologous protein and glucose-regulated protein-78 in SKOV3 cells.
Phosphorylation of H2AX, a marker of DNA double-strand breaks (DSBs) was found to be
enhanced in cells administrated with myricetin. The data designated that myricetin induces
DNA DSBs and ER stress, which leads to apoptosis in ovarian cancer SKOV3 cells [95].
3.9. Breast Cancer
The apoptotic role of myricetin was investigated on breast cancer cells (MCF-7) to
evaluate its possible mechanisms of action. The BAX /Bcl-2 ratio as well as the expression
Int. J. Mol. Sci. 2023,24, 9665 13 of 31
of BRCA, p53, and GADD45 genes and expression levels of apoptosis-associated genes
caspase-3, caspase-8, and caspase-9 were meaningfully enhanced following the exposure
of breast cancer cells with myricetin. Myricetin efficiently brings apoptosis in breast
cancer cells via inducing both intrinsic and extrinsic apoptotic pathways. Myricetin might
causes its apoptotic effects on breast cancer (MCF-7) cells through encouraging the BRCA1-
GADD45 pathway [
96
]. Another study indicated that myricetin stimulated the production
of hydrogen peroxide (H
2
O
2
) in culture medium devoid of cells as well as in the presence
of normal cells and triple-negative breast cancer cells. Furthermore, deferiprone-mediated
inhibition of intracellular ROS generation via the iron-dependent Fenton reaction and
inhibition of extracellular reactive oxygen species (ROS) accumulation with superoxide
dismutase plus catalase inhibited myricetin-induced cytotoxicity in triple-negative breast
cancer cell cultures. It was concluded that the cytotoxic effect of myricetin on triple-negative
breast cancer cells was through oxidative stress initiated via extracellular H
2
O
2
produced
by autoxidation of myricetin [97].
Myricetin showed an important role in the enhancement of the antioxidant levels
in plasma, breast tissue and erythrocyte lysate, and was powerful in inhibiting the ox-
idative damage caused by the 12-dimethylbenzanthracene (DMBA). Myricetin (50, 100,
and 200 mg/kg/oral) treated animal caused comparable outcomes to that of standard
vincristine as well as control groups. Myricetin was found to be either equieffective or
more powerful than vincristine in all studied parameters [
98
]. The cancer preventive role
of myricetin were established in SK-BR-3 cells (human breast cancer cells). The viability of
the cells decreased as myricetin concentration was increased, and apoptosis and apoptotic
bodies significantly increased. Furthermore, levels of Bcl-2 were decreased and cleaved
PARP and Bax proteins increased. While phosphorylated extracellular regulated kinase
(pERK) expression levels were down, they were up for phosphorylated mitogen activated
protein kinases (p-p38) and c Jun N terminal kinase (JNK). Besides that, the relationship
between cell viability and autophagy in cells administered with myricetin was investigated
using 3 methyladenine (3 MA). The findings demonstrated that breast cancer cells were en-
couraged to undergo apoptosis when given methyladenine and myricetin simultaneously.
A JNK inhibitor treatment also reduced cell viability, promoted the expression of Bax, and
reduced the expression of p JNK, Bcl 2, and LC 3 II/I [99].
3.10. Cervix Cancer
Investigations were conducted into the anticancer potential of myricetin, methyl
eugenol, and cisplatin (CP), both individually and together, against cervical cancer cells.
The findings showed that, in contrast to single drug therapy, the combined effect of methyl
eugenol or myricetin with CP induced a stronger impact through provoking apoptosis and
preventing growth of cancer cell. The combination of myricetin or methyl eugenol with
CP lead to more strong induction of apoptosis. Comparing the treatment with a single
drug to the combination treatment, the quantity of cells in the G0 stage increased in case of
combination treatment. Caspase-3 activity and mitochondrial membrane potential loss was
considerably greater in combined therapy in comparison to treatment of individual drug.
The findings of this study support the idea that myricetin and methyl eugenol administered
in combination with cisplatin could be a feasible clinical chemotherapeutic strategy for
treating human cervical cancer [100].
3.11. Lung Cancer
According to a recent study, myricetin was found to inhibit PD-L1 expression in
human lung cancer cells that is brought on by IFN. Both the expression of IDO1 and
kynurenine production are lowered. Additionally, myricetin restored the survival, pro-
liferation, expression of CD69, and secretion of interleukin-2 in Jurkat-PD-1 T cells that
had been suppressed by IFN-exposed lung cancer cells. Myricetin targeted and blocked
the JAK-STAT-IRF1 axis, which was the mechanism by which IFN-upregulated PD-L1 and
IDO1 at the transcriptional level [
101
]. The xenografts were created by transplanting A549
Int. J. Mol. Sci. 2023,24, 9665 14 of 31
cells into immunodeficient mice. In the S4-2-2 (5,7-dimethoxy-3-(4-(methyl(1-(naphthalen-
2-ylsulfonyl) piperidin-4-yl amino butoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one)
given group, the tumor weight attenuated and tumor volume inhibition rate was 41.9%
than the DMSO group. Additionally, the tumor burden that given S4-2-2 treatment was
lower than that in the DMSO control mice. Besides, number of apoptotic cells enhanced
after S4-2-2 treatment. Furthermore, invasiveness of A549 cells was prevented and number
of migrating cells was decreased after S4-2-2 treatment [102].
After myricetin therapies, A549 and NCI-H446 cells were looked at using a microscope
to detect cell swelling and empty cell membranes. Transmission electron microscopy
also revealed the existence of multiple pores, another hallmark of pyroptosis, with in cell
membranes of myricetin-treated A549 cells and NCI-H446. When considered as a whole,
the results show that myricetin causes pyroptosis in NCI-H446 and A549 cells by cleaving
GSDME rather than GSDMD [
103
]. Cytotoxic potential of myricetin in A549 as well as
A549-IR cells were examined. A549 IR cells treated with myricetin showed a negligibly
cytotoxic activity 48 h after incubation. Additionally, myricetin was found to inhibit the
migration of A549-IR cells in a concentration dependent manner. Furthermore, it was
observed that A549 IR cells expressed more slug, MMP9, vimentin, and MMP2 while
expressing less E-cadherin. Surprisingly, myricetin treatment in A549 IR cells did not
significantly increase E-cadherin expression. Slug, MMP2, MMP9, and vimentin expression
was all significantly reduced in A549 IR cells after exposure to 100
µ
M myricetin, in
contrast to E-cadherin [
104
]. Evaluation of the effects of myricetin in combined application
with radiotherapy on improving radiosensitivity of lung cancer A549 and H1299 cells.
After receiving X-ray exposure
in vitro
, the myricetin-treated groups showed signs of
significantly suppressed cell surviving fraction and proliferation, increased Caspase-3
protein expression, and increased cell apoptosis in comparison to the exposed group
without myricetin treatment. The results of the
in vivo
assay revealed that myricetin
treatment of radiation-exposed mice reduced the growth rate of tumour xenografts [105].
3.12. Oral Cancer
The oral squamous cell carcinoma SCC-25 and HaCaT cell lines were used to test the
anticancer activity of myricetin and naringenin. Myricetin and naringenin both inhibited
the growth of SCC-25 cells, but naringenin only targeted cancer cells while leaving HaCaT
cells unaffected. Myricetin and naringenin inhibited cell proliferation, but this was not
due to the induction of apoptosis; rather, it was due to cell cycle disruption, as G2/M
and G0/G1 blockages were noted after 24 h of treatment in HaCaT and SCC-25 cells,
respectively. Besides, myricetin induced a reduction of Cyclin B1 in HaCaT and Cyclin
D1 in SCC-25 cells. Myricetin and naringenin were both found to be able to decrease
the motility of HaCaT and SCC-25 cells in assays for wound healing and cell invasion.
The results of the study demonstrate the cancer preventive potential of myricetin.as well
as naringenin on oral squamous cell carcinoma as they employ cytostatic effect via the
impairment of cell cycle progression. Consequently, naringenin and myricetin seem as
hopeful candidate as oral cancer chemo preventive agents [106].
3.13. Lymphoma
The anticancer potential of myricetin was investigated based on lymphoma. By
directing bruton tyrosine kinase, myricetin was reported to be more sensitive to human
diffuse large B lymphoma cell TMD-8 than other tumor cells (BTK). The HTRF assay
demonstrated that myricetin inhibited BTK kinase and that it could interact with key
residues including Leu408, Thr474, and Ala478 in the BTK active pocket, prevent the
autophosphorylation on tyrosine 223, block BTK/AKT signal transduction cascades, and
inhibit BTK/ERK. Cell cycle, autophagy, and apoptosis results showed that myricetin could
cause the arrest G1/G0 cycle by regulating cyclin B1/D1 expression, initiate autophagy,
and cause apoptosis by elevating the ratio of Bax/Bcl-2. Oral myricetin administration
significantly inhibited the growth of the TMD-8 xenograft tumour
in vivo
without causing
Int. J. Mol. Sci. 2023,24, 9665 15 of 31
any negative side effects. Myricetin may also cause tissue lymphoma cells to proliferate
less and stimulate apoptosis [107].
3.14. Leukemia
Treatment with myricetin exhibits potent pro-apoptotic and anti-proliferative effects on
K562 human leukemia cells in a concentration-dependent means. Significantly, exogenous
addition of guanosine clearly lowered the cytotoxic effects of myricetin on leukemia cells
(K562) cells. Overall, these findings show effective anti-leukemia activity of myricetin
because it inhibits the biosynthesis of purine nucleotides by suppressing the catalytic
potential of hIMPDH1/2 [
108
]. Myricetin derivatives such as the 3, 7, 4
0
, 5
0
- tetramethyl
ether of myricetin (1), isolated from the hexane extract of Cistus monspeliensis, and its
3
0
, 5-diacetyl derivative (2) which was prepared, and the pure compound, myricetin (3),
were evaluated for their
in vitro
cytotoxic potential against human leukemic cell lines.
Compound
2
showed greater cytostatic as well as cytotoxic activities as compared to
compound 1, whereas compound 3was not active against all used cell lines [109].
3.15. Bladder Cancer
The least concentration of myricetin was found to have an impact on cell viabil-
ity in a bladder cancer study. Myricetin treatment negatively affected cell viability in a
concentration- and time-dependent manner. In addition, cells subjected to myricetin (40 or
80
µ
M) showed significantly decreased rates of cell growth. Additionally, myricetin treat-
ments resulted in a concentration arrest of the cell cycle in the G2/M phase for the bladder
cancer cell (T24). The control cells displayed intact nuclei, as shown by the microscopic
images, whereas the myricetin (40 or 80
µ
M)-treated cells displayed significant nuclear
fragmentation, that is indicative of apoptosis. An
in vivo
study showed that the tumor
growth rate in the myricetin group was lower than that of the control group. According
to the findings, myricetin treatment at a dose of 5 mg/kg per day had antitumor effects
on bladder cancer xenografts
in vivo
. Additionally, myricetin treatment demonstrated a
greater rate of survival in comparison to the control group [110].
3.16. Thyroid Cancer
The proliferation of human anaplastic thyroid cancer (HATCs) cell was reported to
be significantly reduced by myricetin nearly 70%. Besides, a significant percentage of
dead cells have displayed the arrest of sub-G1 phase. In addition, myricetin demonstrated
cytotoxicity and caused condensation of DNA in concentration-dependent ways in human
anaplastic thyroid cancer (SNU-80) cells. The stimulation of caspase cascades and the
Bax: Bcl-2 ratio at a concentration of 100 µM were both increased involving the myricetin-
induced cell death mechanism. Along with altering the mitochondrial membrane potential,
myricetin promoted the discharge of an apoptosis-inducing factor into the cytosol from
mitochondria [
63
]. Another study showed that myricetin, in a concentration-dependent
manner, caused DNA condensation and cytotoxicity in SNU-790 human papillary thyroid
cancer (HPTC) cells. Myricetin also increased the expression ratio of Bax:Bcl-2 and caspase
cascade activation. Additionally, myricetin changed the potential of the mitochondrial
membrane and started the secretion of the apoptosis-inducing component or factor. These
findings support the notion that myricetin causes SNU-790 papillary thyroid cancer cells to
die, suggesting that it may be useful in the emergence of therapeutic agents for treating
thyroid cancer in humans [111].
3.17. Bone Cancer
Osteosarcoma is the most common form of bone cancer. It has been reported that
proliferation and DNA replication decreased with myricetin treatment, whereas it increased
apoptotic DNA fragmentation in canine osteosarcoma cell lines, DSN and D-17. Moreover,
it enhanced generation of ROS, depolarization of MMP and lipid peroxidation, in both used
cells. In canine osteosarcoma cells, myricetin intervention stimulated the phosphorylation
Int. J. Mol. Sci. 2023,24, 9665 16 of 31
of p90RSK, p70S6K, AKT, JNK, and ERK1/2. As a result, it was concluded that myricetin
could be a highly promising and less harmful treatment approach for the prevention and
regulation of canine osteosarcoma progression [112].
3.18. Skin Cancer
There are three main types of skin cancer as melanoma, basal cell carcinoma and
squamous cell carcinoma. In epidermal JB6 P+ cells of mouse skin, myricetin inhibit the
expression of Cox-2 that is brought on by UVB exposure. Besides, the treatment with
myricetin prevented NF-
κ
B activation brought on by UVB in a dose-dependent manner as
well as activator protein-1 activation. Moreover, myricetin prevented Fyn kinase activity
as well as then reduced UVB-induced phosphorylation of MAPK. Myricetin was found
to directly inhibit Fyn kinase activity in mouse skin
in vivo
, which in turn reduced UVB-
induced Cox-2 expression. The results of the mouse skin tumorigenesis study clearly
showed that pre-treatment with myricetin significantly and concentration-dependently
reduced the incidence of UVB-induced skin tumours. Overall, these finding designated
that myricetin show powerful chemopreventive potential principally by targeting Fyn in
skin carcinogenesis [
113
]. The anticancer capacity of myricetin has been explored in A431
cell lines of skin cancer. Myricetin has found to have potential anticancer effects against
skin A431 cancer cell lines. It had been reported that anticancer properties of myricetin
were a consequence of modifications in the membrane potential of mitochondria brought
on by ROS and the start of apoptosis. Besides, the response to myricetin treatment resulted
in modifications to the Bcl-2 and Bax expressions. In addition to inducing cell cycle arrest
in A431 cells, myricetin was further explored to prevent migration and invasion. These
findings suggest that myricetin might be an important lead molecule for the discovery of a
successful skin cancer therapeutic strategy [114].
3.19. Myeloma
Myricetin (10
µ
M and 20
µ
M) forms showed negligible degrees of genotoxicity in
lymphocytes of multiple myeloma patients in contrast with lymphocytes from healthy
individuals, according to an
in vitro
study. In addition, western blot results showed that
lymphocytes from myeloma patients had higher p53 protein levels and lower Bcl-2/Bax
ratios than did lymphocytes from healthy people. The regulation of apoptotic proteins
activated by myricetin exposure in lymphocytes of myeloma patients occurred via P53
as well as oxidative stress-dependent pathways, as evidenced by the notable increase in
intracellular reactive oxygen species level [115].
3.20. Brain Cancer
The ability of myricetin to inhibit the proliferation of glioma cells of human (U251)
was investigated while also assessing how it affected the production of ROS, the cell cycle,
apoptosis, apoptosis-related proteins, and cell migration. Growth inhibitory potential of
human glioma cells was observed by myricetin treatment as dose-dependent and time
dependent. U251 cells treated with myricetin became detached from surrounding cells,
causing clusters of cells to move around in the medium. Besides, apoptotic cell death was
initiated by treatment of myricetin. The percentage of early as well as late apoptotic cells
increased after treatment with myricetin. Additionally, after myricetin treatment, there was
a concentration-dependent reduction in the expression of Bcl-2 and Bcl-xl as well as a raise
in Bad and Bax levels. The use of this medication resulted in an arrest of cell cycle in the
G2/M phase [116].
In a separate study, myricetin, tumour necrosis factor-related apoptosis-inducing
ligand (TRAIL), or both compounds were applied to human astrocytes and glioblastoma
cells. Glioma cells quickly underwent apoptosis when treated with subtoxic doses of
myricetin in combination with TRAIL. Remarkably, combined treatment consisting of
myricetin and TRAIL were not affected on human astrocytes. Combined treatment with
myricetin as well as TRAIL improved the effector caspases-3/-7 and activation of initiator
Int. J. Mol. Sci. 2023,24, 9665 17 of 31
caspases-8/-9. Furthermore, over-expression of the short isoforms of bcl-2 and c-FLIP
(S) lowered the level of apoptosis induced by the combination of TRAIL and myricetin.
In addition, myricetin decreased the degree of expression of both the long and short
isoforms of bcl-2 and c-FLIP. Bcl-2 and the short isoform of c-FLIP were reported to be
the chief regulators of death of malignant glioma cell associated with TRAIL-myricetin
treatment [117].
Table 2. Role of myricetin in different types of cancer.
Cancer Type Dosage Findings Refs.
Prostate cancer
0, 25, or 50 µmol/L Myricetin inhibits migration, invasion, and the EMT in PCa cells. [60]
50 µMMyricetin inhibits the demethylation activity of KDM4A, KDM4B,
and KDM4C [82]
Colon cancer
100 µM
In comparison to controls, treatment with 100 µM of myricetin
induced about 70% reduction in cell viability. Furthermore,
treatment of HCT-15 with 100 µM of myricetin induced significant
nuclear rounding and shrinkage of HCT-15 human colon cancer
cells in comparison to controls
[85]
0–200 µM
The results demonstrate that HCT-15 cell viability rate to be 100%,
36.8%, 35%, and 31.4% in cells treated with 0, 100, 150, and 200
µ
M
myricetin, respectively. Whereas, the viability rates of CCD-18co
cells showed 100%, 78.9%, 76.1%, and 49.9% at 0, 100, 150, and
200 µM myricetin, respectively
[86]
50 and 100 µmol/L
Light microscopy-based results showed that the apoptotic cells
became rounder and smaller. Moreover, there were vesicles in the
cell membrane and apoptotic bodies in the cell. The percentage of
apoptotic cells was 28.5 and 67.4%.
[57]
Liver cancer
0, 100 or 200 µM
Myricetin treatment significantly decreased cell growth and
induced visible cell death in HCC cells. Treatment of HepG2 and
Huh-7 cells markedly inhibited cell growth. Furthermore,
myricetin-treated HepG2 cells showed increased apoptosis rate
compared to control cells. Similar effects of myricetin on apoptosis
were detected in Huh-7 cells.
[88]
100 µM
The cell scratch assay indicated that compared with the control
group, the migration of MHCC97H cells was inhibited when the
cells were treated for 24 and 48 h. Furthermore, real
time-quantitative polymerase chain reaction (RT-qPCR) analysis
showed that the relative mRNA expression of E-cadherin in
MHCC97H cells significantly enhanced at 25
µ
M myricetin and the
relative mRNA expression level of N-cadherin significantly
reduced at 100 µM, along with that of vimentin
[89]
0–50 µM
HCC cells treated with myricetin were incubated with the CCK-8
reagent. The results showed that the viability of these cancer cells
treated with this compound was obviously declined in a
dose-dependent manner
[61]
Gastric cancer 0–30 µM
The cell viability of gastric cancer cells was determined after 24 h of
treatment with 0–30
µ
M myricetin. The cell viability of these cancer
cells was 95.8% with 5 µM myricetin, 90.3% with 10 µM myricetin,
80.6% with 15 µM myricetin, 64.6% with 20 µM myricetin, 52.7%
with 25 µM myricetin, and 36.3% with 30 µM myricetin.
Furthermore, apoptotic bodies in these cancer cells at dose of of 0,
15, and 25
µ
M for 24 h, showed a significant increase in the number
of apoptotic bodies.
[58]
Int. J. Mol. Sci. 2023,24, 9665 18 of 31
Table 2. Cont.
Cancer Type Dosage Findings Refs.
20 and 40 mol/L
The effect of myricetin on apoptosis in HGC-27 and SGC7901 cells
was determined. It was observed that the percentage of apoptotic
cells was higher. As the concentration of myricetin increased, the
percentage of apoptotic cells increased. Furthermore, the
anti-apoptotic protein Bcl-2 and pro-caspase-3 were significantly
decreased and increased concentration of myricetin increased the
degree of low expression.
[64]
Pancreatic
cancer 0, 12.5–200 µM
It significantly reduced cell viability in all pancreatic cancer cells
tested. In addition, incubation of MIA PaCa-2 and S2-013 in culture
medium containing myricetin for 6 h resulted in a statistically
significant increase in caspase-3 and 9 activities.
[90]
Bile duct cancer 5, 10 and 25 µM
The treatment of myricetin for 24 h inhibited migration and
invasion of KKU-100 cells by restraining the phosphorylation of
STAT3 and its downstream factors including ICAM-1 and MMP-9
as well as some inflammatory-associated genes such as iNOS
and COX-2
[49]
Esophageal cancer
0–100 µM
Treatment of the EC9706 cells with different concentration 5-FU
alone could lead to inhibition effect on clonogenic survival.
However, when combined with different concentration of
myricetin, the surviving fraction decreased significantly
[66]
20 or 40 µM
It resulted in the inhibition of the proliferation of EC9706 and
KYSE30 cells in a dose- and time dependent manner. EC9706 and
KYSE30 cells were treated with myricetin and DMSO and were
placed in a transwell chamber. The fraction of KYSE30 cells in the
G0/G1 phase of the cell cycle in the 20 µM myricetin, 40 µM
myricetin, and DMSO groups were 65.41, 70.93, and
56.38%, respectively
[67]
Ovarian cancer
10, 20 and 40 µM
ROS levels in SKOV3 cells were significantly reduced by myricetin
in a dose dependent manner. Relative to controls, intracellular
MDA was significantly reduced dose-dependently by myricetin,
while SOD levels increased significantly. LDH levels in the culture
medium also reduced significantly
[69]
25 µM
Induction of apoptosis in A2780 and OVCAR3 cells was observed.
In A2780 cells treated with myricetin, an ~2.5-fold increase in the
apoptotic signal was observed, whereas, the apoptotic signal was
increased by ~4-fold in OVCAR3 cells.
[59]
40 µg/mL The nuclei of myricetin-treated cells appeared more condensed,
when compared with the untreated cells [95]
Breast cancer
54 µMThe results showed a significant increase in the apoptosis rate in
MCF-7 cells treated with myricetin. [96]
0, 5, 10, 15, 20, and
25 µM
The SK-BR-3 cells treated with different doses of myricetin
exhibited viabilities of 96.5% at 5 µM, 78.1% at 10 µM, 51.4% at
15
µ
M, 42.5% at 20
µ
M, and 37.9% at 25
µ
M. Thus, the SK-BR-3 cells
showed a dose-dependent decrease in viability compared to that of
the control group
[99]
Cervix cancer 10–100 µMCell viability with different treatments in addition to myricetin
showed decreased cell viability [100]
Lung cancer 30 µM
Myricetin significantly inhibited cell migration and invasion of cells
from the upper chamber to the lower chamber, and inhibited the
invasion of cells were significantly higher than that in the
control group.
[103]
Int. J. Mol. Sci. 2023,24, 9665 19 of 31
Table 2. Cont.
Cancer Type Dosage Findings Refs.
Oral cancer 50–250 mM
SCC-25 proliferation was inhibited, in fact, for doses above 150 mM
decrease of cell viability to values below 40%. After 72 h, the
growth inhibitory effect persisted for the highest concentration of
myricetin (250 and 200 mM), whereas for the intermediate dose,
myricetin 150 mM, a partial restoration of cell viability
was observed
[106]
Lymphoma 5, 10, 20, and 40 µM
Myricetin arrest the cell cycle in the G1/G0 phase in a
dose-dependent manner, and the proportion of cells in the S phase
was decreased. Precisely, treatment with 40 µM myricetin
meaningfully increased the proportion of cells in the G1/G0 phase
from 43.00
±
1.25% to 62.67
±
4.95%, and the proportion of cells in
the S phase decreased from 37.10 ±0.52% to 25.30 ±1.05%
[107]
Leukemia 20 and 50 µMIt displayed an arrest of cells in the S-phase in a
dose-dependent manner. [108]
Bladder cancer 20–100 µM
Reduction in cell viability with myricetin treatment at
concentrations of after 12 h ranged from 2.6% to 61%, whereas after
24 h and 48 h ranged from 2.9% to 70% and 3% to 80%, respectively.
However, treatments with myricetin (0–80
µ
M) for 24 h resulted in
a dosage-dependent arrest of T24 cells in G2/M phase of cell cycle.
[110]
Thyroid cancer
0–100 µM
It reduced cell viability of SNU-80 HATC cells in a dose-dependent
manner. In comparison to the control cell treated with 100 µM of
myricetin induced about 85% reduction in cell viability on SNU-80
HATC cells
[63]
25 to 100 mM
It was cytotoxic to SNU-790 HPTC cells in a dose-dependent
manner at concen- trations range. In comparison with control cells
treated with 100mM myricetin exhibited an approximately 82%
reduction in viability.
[111]
Bone cancer 0–100 µM
It gradually decreased the cell proliferation of D-17 and DSN cells
in a dose dependent manner, as proliferation of D-17 and DSN cells
reduced to 40.3% and 38.2%, respectively, after treatment with
100 µM myricetin, as compared to vehicle-treated control cells
[112]
Skin cancer
2.5–20 µMIt inhibited UVB-induced COX-2 protein expression and promoter
activity in a dose-dependent manner [113]
0–40 µM
It caused apoptotic cell death in A431cells dose-dependently. The
apoptotic A431 cells augmented from 1.25% in control to 46.3% at
40 µM of myricetin.
[114]
Myeloma 10–20 µM
Comet assay demonstrated that myricetin bulk (10 µM) and nano
(20 µM) forms exhibited a non-significant level of genotoxicity in
lymphocytes from multiple myeloma patients when compared to
those from healthy individuals.
[115]
Brain cancer
0, 15, 60 and 120 µM
increasing doses of myricetin, led to dose-dependent increase in
Bax and Bad levels and a dose-dependent decrease in Bcl-2 and
Bcl-xl expression levels
[116]
0–150 µM
Combining TRAIL with Myricetin led to a significant increase in
cleaved fragment of PARP and active cleaved caspase-3/-7/-8/-9 in
both U251 and NCH89
[117]
4. Pharmacokinetic and Strategies to Improve Efficacies of Myricetin
Several studies reconnoiter the pharmacokinetic properties of myricetin using dif-
ferent method. Myricetin has been identified and quantified in rat plasma after oral
and intravenous administration using a precise and sensitive ultra-performance liquid
chromatography-tandem mass spectrometry (UPLC-MS/MS) method. For selectivity, pre-
cision, linearity, accuracy, recovery, stability, and matrix effect, the developed method
Int. J. Mol. Sci. 2023,24, 9665 20 of 31
received approval. Over a broad concentration range of 2–4000 ng/mL, the assay was
validated. Precisions within (intra) and between (inter) days all were under 13.49%, and
the range of accuracy was from 95.75 to 109.80%. In order to analyze a pharmacokinetic
investigation of myricetin after intravenous and oral administrations to rats, the current
methodology was successfully used. Myricetin was found to have an absolute bioavail-
ability of 9.62% and 9.74% at 2 oral concentrations, indicating that it was poorly absorbed
after oral route administration [
118
]. Additionally, factors such as its low water solubility,
decreased stability in gastrointestinal fluid, and rapid
in vivo
biotransformation could all
contribute to its low absorption [
119
]. The role of myricetin on the pharmacokinetics of
losartan and its active metabolite, EXP-3174, were examined in rats. After oral adminis-
tration of losartan (0.4, 2 and 8 mg/kg) to rats in the condition of having or not having of
myricetin, the pharmacokinetic parameters of both losartan and EXP-3174 were assessed. It
was evaluated how myricetin affected the activity of CYP2C9, CYP3A4, and P-glycoprotein.
CYP2C9 and CYP3A4 enzyme potential were inhibited by myricetin at concentrations
of 50% inhibition of 13.5 and 7.8
µ
M, respectively. In addition, myricetin significantly
and concentration-dependently increased the cellular accumulation of rhodamine 123 in
MCF-7/ADR cells overexpressing P-glycoprotein. Myricetin have been found to signifi-
cantly alter the pharmacokinetic parameters of losartan in contrast to the control group.
Losartan’s peak plasma content increased by 31.8–50.2% and the area under the plasma
concentration-time curve by 31.4–61.1%, respectively, when myricetin (2 or 8 mg/kg) was
present. As a result, in comparison to the control, myricetin significantly increased the
absolute bioavailability of losartan. Further evidence that myricetin could inhibit the
CYP-mediated metabolism of losartan to its active metabolite was provided by the 20%
reduction in the metabolite-parent area under the plasma concentration-time curve ratio
that was caused by concurrent use of the myricetin drug [120].
Its pharmacological potential in several diseases have been confirmed including can-
cer through modulation of cell signalling molecules activities. Irrespective of its potential
benefits, its role in diseases management is limited due to low bioavailability and low
absorption, quick elimination. Accordingly, a number of discoveries were demonstrated
to get around the problems caused by poor bioavailability, low absorption, and quick
elimination. Different types of nano-formulation and its role in the improvement of its
efficacies are described (Table 3). Nano based formulation has been prepared and their
role in cancer inhibition tested and result confirms that these formulations can be em-
ployed as delivery to improve the bioavailability of this compound. Polymeric carrier
based on chitosan-functionalized Pluronic P123/F68 micelles loaded with myricetin was
prepared to expand the therapeutic index of chemotherapy of glioblastoma cancer. The
outcomes confirmed that myricetin-loaded micelles (MYR-MCs) displayed enhanced cel-
lular uptake as well as antitumor potential as compared to free myricetin
in vitro
, with a
meaningfully improved anticancer potential in vivo subsequent effective transport across
the blood-brain barrier. However, myricetin-loaded micelles did not disturb the barrier
function, brain endothelial, the liver, kidneys or heart. In addition, myricetin-loaded mi-
celles altered the expression of apoptotic proteins in mice. In conclusion, myricetin-loaded
micelles may be measured an active as well as hopeful drug delivery system in the glioblas-
toma treatment [121]. A combination of multidrug resistance protein (MRP-1) siRNA and
myricetin (Myr)-loaded mesoporous silica nanoparticles (MSN) was created. In comparison
to non-targeted nanoparticles, folic acid-conjugated nano-formulations showed a signifi-
cant uptake in lung cancer cells.
In vitro
research on drug release suggested that sustained
release in folic acid-conjugated mesoporous silica nanoparticles (MSN) with myricetin and
MRP-1 nanoparticles was preferable to free myricetin and MSN combined with multidrug
resistance protein (MRP-1)/Myr. The viability of the lung cancer cell lines was noticeably
decreased by treatments using FA-conjugated MSN in combination with myricetin and
MRP-1, which was accompanied by a decreased rate of colony formation. In addition,
myricetin and MRP-1-loaded mesoporous silica nanoparticles significantly induced apop-
tosis in cells of lung cancer. The ability of FA-conjugated mesoporous silica nanoparticles
Int. J. Mol. Sci. 2023,24, 9665 21 of 31
with myricetin and MRP-1 nanoparticles to accurately gather at tumour sites was demon-
strated by
in vivo
fluorescence research. FA-conjugated MSN equipped with myricetin and
MRP-1 nanoparticles have been suggested to more effectively inhibit tumour growth with
negligible adverse consequences when compared to standard myricetin and mesoporous
silica nanoparticles coupled to MRP-1/Myr nanoparticles [
122
]. Myricetin-loaded NLCs
was reported to reduce cell viability by 50
±
2.3 to 40
±
1.3%. Myricetin-loaded NLCs
and docetaxel administered together resulted in a higher percentage of breast cancer cells
undergoing apoptosis (MDA-MBA231). Proapoptotic factor Bax and Bid mRNA rates in-
creased in response to expression of antiapoptotic genes, while proapoptotic factor Bax and
Bid rates markedly decreased. Finally, evidence suggests that the NLC delivery mechanism
may be a promising strategy for enhancing the impact of anticancer drugs like docetaxel
on breast cancer [123].
Table 3. Nano-formulation and its role in cancers.
Nanoformulation/
Derivatives Cancer Findings Refs.
Myricetin-loaded micelles Glioblastoma
Myricetin-loaded micelles showed role in the enhancement of
cellular uptake and antitumor potential in comparison of
free myricetin
[121]
FA-conjugated MSN
combined with myricetin
as well as MRP-1
Lung cancer This formulation significantly reduced the cell viability, and
caused induction of apoptosis in lung cancer cells [122]
Myricetin-loaded NLCs Breast cancer NLC delivery vehicle may be an encouraging strategy to
enhance the efficacy of docetaxel on breast cancer. [123]
Myricetin-solid lipid
nanoparticles Lung cancer Enhanced antitumor potential and 3-fold in IC50 [124]
Myricetin-gold
nanoparticles Breast cancer Myricetin- gold nanoparticles showed great potential against
breast cancer [125]
FA-Myr-BSA NPs Breast cancer This nanoformulation efficiently reduced the cancer
cells viability. [126]
S4-10 Lung cancer
Myricetin derivatives, has displayed the highest antitumor
efficacy in dose-dependent manner. The proliferation of A549
cells were significantly attenuated by S4-10 in both
in vitro
and
in vivo assays.
[127]
S4-2-2 Lung cancer
Different myricetin were synthesized and tested. Experiments
on non-small cell lung cancer (NSCLC) showed that S4-2-2
(5,7-dimethoxy-3-(4-(methyl(1-(naphthalen-2-ylsulfonyl)
piperidin-4-yl) amino)
butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one) had the
strongest effect on A549 cell inhibition across all compounds.
[102]
3, 7, 40, 50-tetramethyl
ether (1)
and
3
0
, 5-diacetyl derivative (2)
Leukemia
Two myricetin derivatives, were examined for their in vitro
cytotoxic activity against human leukemic cell lines. Compound
2exhibited higher cytostatic and cytotoxic activities in
comparison to compound 1with vinblastine used as a control.
[109]
M10, a novel derivative of
Myricetin Colorectal cancer
Oral administration of this derivative M10 exerts
chemoprevention of ulcerative colitis and colorectal tumor
in mice
[128]
Microparticles containing myricetin solid lipid nanoparticles (SLNs) were prepared
for lung cancer therapy. Greater antitumor potential of myricetin-phospholipid-complex as
well as 3-fold decrease in IC
50
were accomplished with myricetin- solid lipid nanoparticles.
This might be related to increased fluorescence intensity and greater cellular uptake as
seen by confocal imaging. Spray-drying was used to create respirable microparticles from
solid lipid nanoparticles encasing MYR-PH-CPX. In addition to good flowability and >80%
Int. J. Mol. Sci. 2023,24, 9665 22 of 31
release over 8 h, the latter validated MMAD of 2.39 mm and a span index of 1.84. The study
emphasizes the phospholipid-ability complexes to encapsulate myricetin at the nanoscale,
its antitumor properties, and its cellular uptake. Possibilities for efficient lung carcinoma
treatment are provided by the formulation of respirable microparticles [124].
Another recent study was performed to prepare a simple as well as stable synthesis
of gold nanoparticles (AuNPs) with myricetin via ultrasound-assisted method. Result
revealed that anticancer potential by myricetin- gold nanoparticles -treated cells displayed
a good proportion of dead cells demonstrated with formation of pro-apoptotic bodies.
Furthermore, myricetin-AuNPs showed depolarization of mitochondrial membrane poten-
tial as well as production of ROS. This study evidences that myricetin-gold nanoparticles
(NPs) hold great potential to use against breast cancer as a strong anticancer drug [
125
]. To
encapsulate myricetin, folic acid (FA)-conjugated bovine serum albumin (BSA) NPs were
used. It was investigated how to deliver myricetin to breast cancer cells that were folate
receptor-positive using naturally overexpressed folate receptor. The viability of the MCF-7
cells was effectively decreased by FA-myricetin-BSA NPs. Additionally, this formulation
increased myricetin uptake in MCF-7 cells. Following incubation, it was possible to see
the typical distorted membrane bodies and condensed nuclei associated with apoptosis.
The observed outcomes demonstrate that the newly created FA-myricetin-BSA NPs may
serve as a potential myricetin carrier to enhance the anticancer potential of this anticancer
drugs [126].
5. Synergistic Effects of Myricetin with Anti-Cancer Drugs
Anti-cancer drugs show a significant role in cancer treatment but their potential role
is restricted due to their adverse effects. Natural compounds either native or its bioactive
compound enhance the activity of anti-cancer drugs based on various cancer cells via
synergistic antitumor effect with less or no toxic effects. To determine if myricetin can
increase the ability of paclitaxel to act as a chemotherapeutic agent. In direction to examine
whether myricetin is capable to improve the chemotherapeutic potential of paclitaxel.
Synergistic effects of myricetin with anti-cancer drugs are described below (Table 4and
Figure 4, refs. [59,70,92,100,129]).
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 24 of 32
Prostate cancer C4-2B Enzalutamide
The combination of PLGA-encapsulated myri-
cetin with enzalutamide is potentially effective
for castration-resistant prostate cancer
[82]
Cervical cancer HeLa Methyl eugenol
Combination of myricetin or methyl eugenol
with cisplatin resulted in more potent apopto-
sis induction.The combination treatment also
increased the number of cells in G0/G1 phase
dramatically as compared to single drug treat-
ment.
[100]
Lung cancer A549 cucurbitacin E
Cucurbitacin E-myricetin (CuE: 0.5 μM, myri-
cetin: 20 μM), a combination of these com-
pounds inhibited lung cancer cell proliferation
and colony formation, and induced apoptosis
and cell cycle arrest in the G0/G1 phase, exhib-
iting a synergistic effect.
[130]
Figure 4. Synergistic effects of myricetin with anti-cancer drugs.
In order to investigate whether myricetin is able to enhance the chemotherapeutic
potential of paclitaxel (PTX), the ovarian cancer cells were treated with a sub-lethal con-
centration of myricetin (5 μM) for 48 h, and then incubated with a sub-lethal concentration
of paclitaxel (100 nM). The findings showed that paclitaxel (100 nM) did not significantly
promote cytotoxicity in the cell types used. However, a discernible decline in cell viability
was observed when the myricetin-treated cells were further incubated with paclitaxel (100
nM). Thus, the combined treatment of paclitaxel and myricetin was effective in used cell
lines, resulting in a loss of cell viability of approximately 50% [59]. It was investigated
whether myricetin could improve the radiosensitivity of lung cancer H12 99 and A549 cells
when used in combination with radiotherapy. Relying on in vitro study, the groups ad-
ministered with myricetin showed significantly reduced cell surviving percentage as well
as improved cell apoptosis, proliferation, and elevated Caspase-3 protein expression in
comparison to the exposed population not having myricetin therapies.
In vivo research also showed that myricetin treatment of radiation-exposed mice sig-
nificantly slowed the growth of tumour xenografts [105]. Myricetin or methyl eugenol
combined with cisplatin had a positive influence than either drug alone at inhibiting can-
Figure 4. Synergistic effects of myricetin with anti-cancer drugs.
Int. J. Mol. Sci. 2023,24, 9665 23 of 31
Table 4. Synergistic effects of myricetin with anti-cancer drugs.
Cancer Cell Lines Anti-Cancer
Drugs/Treatment Type Outcome of the Study Refs.
Ovarian cancer A2780 and OVCAR3 Paclitaxel
When 100 nM paclitaxel was added to
myricetin-exposed cells, there was a significant
decline in cell viability.
[59]
Lung cancer A549 cells and H1299 Radiotherapy
Myricetin and radiotherapy together can make
pulmonary carcinoma tumors more
radiosensitive.
[105]
Cervix cancer HeLa Cisplatin
Myricetin, cisplatin, and methyl eugenol, when
used in combination, significantly increased the
percentage of cells in the G0/G1 phase
compared to when used alone.
[100]
Leukemia and
hepatoma HL-60 and HepG2 Piceatannol
The proportion of apoptotic HL-60 (leukaemia)
cells was substantially greater in the
combination therapy.
Only after piceatannol treatment did the
percentage of TUNEL-positive HepG2 cells rise
significantly; while combined treatment was
used, it was even lower compared to
piceatannol-only-treated cells.
[129]
Choriocarcinoma
JAR and JEG-3
Etoposide and cisplatin
Myricetin showed synergistic antiproliferative
effects with chemotherapeutics, etoposide as
well as cisplatin
[70]
Esophageal
carcinoma EC9706 5-fluorouracil
The groups given myricetin and 5-fluorouracil
together showed significantly reduced cell
survival percentage and proliferation, as well as
increased apoptosis.
[92]
Prostate cancer C4-2B Enzalutamide
The combination of PLGA-encapsulated
myricetin with enzalutamide is potentially
effective for castration-resistant prostate cancer
[82]
Cervical cancer HeLa Methyl eugenol
Combination of myricetin or methyl eugenol
with cisplatin resulted in more potent apoptosis
induction.The combination treatment also
increased the number of cells in G0/G1 phase
dramatically as compared to single
drug treatment.
[100]
Lung cancer A549 cucurbitacin E
Cucurbitacin E-myricetin (CuE: 0.5 µM,
myricetin: 20 µM), a combination of these
compounds inhibited lung cancer cell
proliferation and colony formation, and
induced apoptosis and cell cycle arrest in the
G0/G1 phase, exhibiting a synergistic effect.
[130]
In order to investigate whether myricetin is able to enhance the chemotherapeutic
potential of paclitaxel (PTX), the ovarian cancer cells were treated with a sub-lethal concen-
tration of myricetin (5
µ
M) for 48 h, and then incubated with a sub-lethal concentration of
paclitaxel (100 nM). The findings showed that paclitaxel (100 nM) did not significantly pro-
mote cytotoxicity in the cell types used. However, a discernible decline in cell viability was
observed when the myricetin-treated cells were further incubated with paclitaxel (100 nM).
Thus, the combined treatment of paclitaxel and myricetin was effective in used cell lines,
resulting in a loss of cell viability of approximately 50% [
59
]. It was investigated whether
myricetin could improve the radiosensitivity of lung cancer H1299 and A549 cells when
used in combination with radiotherapy. Relying on
in vitro
study, the groups administered
with myricetin showed significantly reduced cell surviving percentage as well as improved
Int. J. Mol. Sci. 2023,24, 9665 24 of 31
cell apoptosis, proliferation, and elevated Caspase-3 protein expression in comparison to
the exposed population not having myricetin therapies.
In vivo
research also showed that myricetin treatment of radiation-exposed mice
significantly slowed the growth of tumour xenografts [
105
]. Myricetin or methyl eugenol
combined with cisplatin had a positive influence than either drug alone at inhibiting cancer
cell growth and inducing apoptosis. Further, this combination was found to significantly
increase the induction of apoptosis. In addition, when compared to single drug therapy,
this combination therapy substantially boosted the number of cells in the G0/G1 stage.
In addition, the combined treatment significantly increased the activity of caspase-3 and
mitochondrial membrane potential loss. The results of this study point to myricetin and
methyl eugenol as a potential clinical chemotherapy strategy for treating human cervical
cancer [100].
In (HL-60) leukemia cells, myricetin or piceatannol alone caused apoptotic cell death
in a way that depended on the concentration and the duration of exposure. Likewise, the
percentage of apoptotic (HL-60) leukemia cells was noticeably higher in the combined study
population. After piceatannol therapies, the proportion of TUNEL-positive HepG2 cells
was significant, but it was even lower in the combined treatment than in the piceatannol-
only-treated cells. In summary, (HL-60) leukemia cells-initiated apoptosis in response to
piceatannol and myricetin, but HepG2 cells did not (hepatoma) [
129
]. Choriocarcinoma
cells-based study reported that myricetin showed synergistic antiproliferative potential
with chemotherapeutics, etoposide and cisplatin [
70
]. To determine whether myricetin has
an encouraging inhibitory impact when used together with 5-FU, a study was conducted
using esophageal cancer cells. When compared with the 5-FU group without treatment
of myricetin, 5-FU treated groups with combine with myricetin displayed meaningfully
suppressed cell survival fraction as well as proliferation, apoptosis of cells was increased.
The 5-FU combined with myricetin groups showed a lower cyclin D, survivin, Bcl-2, and
increased caspase-3, p53 expression levels. Furthermore, in an
in vivo
study, mice given
the mixture of 5-FU and myricetin showed a significant reduction in the rate of tumour
xenograft growth [92].
6. Toxicity of Myricetin
Numerous reports have proven that myricetin shows numerous pharmacological activ-
ities including cancer. Myricetin has recognized generally safe. Intraperitoneal-injection of
myricetin at an extreme dose of 1000 mg/kg did not cause death of mice, easing the safety
issue [
131
] and this flavonols at approximately 0.5 LD50 doses suppressed the vascular
endothelial growth factor (VEGF)-stimulated HUVEC tubular structure formation [
132
].
Few reports have reported toxic side effects under specific conditions. Isolated guinea pig
enterocytes were exposed to kaempferol, quercetin, and myricetin in concentrations of
50–450
µ
M. Toxicity was evaluated using trypan blue exclusion and lactic dehydrogenase
(LDH) leakage. Myricetin caused cellular damage at 450
µ
M as compared with a control
incubation; cellular viability was 12–60% lower and LDH leakage 28–41% greater after 3 h
of incubation. Furthermore, quercetin and myricetin, both of which produce superoxide
on autoxidation, seemed to be more toxic than kaempferol [
133
]. Myricetin is susceptible
to autooxidation at pH over than 7.4 which could cause to the release of reactive oxygen
species and can cause a toxic effect on the biomolecules [134].
7. Limitations and Future Prospects
Myricetin possess significant health benefits and despite its recognized role in cancer
management, scanty data is available to support its thorough clinical implications [
135
].
Some major limitations of this compound in the treatment of diseases including cancer
are due to its low water solubility, fast metabolism and quick excretion from the body. In
addition, its role in cancer treatment and prevention is still to be explored thoroughly due
to its low bioavailability. Besides this, the therapeutic challenges of myricetin are its lack of
Int. J. Mol. Sci. 2023,24, 9665 25 of 31
translational studies to know the exact route of administration, and effective dosage for
different cancers.
In recent times, the clinical investigations have started to fulfil the gap between the
research laboratory experiments and their direct clinical implication. The researchers are
now exploring the clinical uses of flavonoids as anticancer agents in different clinical trials.
Furthermore, nano-formulation based flavonoids are gaining interest to target different
tumors to minimize the off-target side effects and enhancing the drug efficacy. However,
all these investigations are under pre-clinical stage [136].
The future prospects of the usage of this compound includes more research to be done
based on different clinical trials to understand the action mechanism, safety, and proper
dosage. Moreover, different challenges should be focused on engineering different nano-
formulations of myricetin to overcome the poor bioavailability, loading capacity, targeted
orientation and premature release of this compound. Furthermore, some derivatives of
myricetin need to be synthesized to check their anticancer potential.
8. Conclusions
Cancer is one of the main culprits of death worldwide. In spite of the progress of
treatment approaches, cancer leftovers a crucial cause of death globally. Moreover, current
mode of treatment of cancer is expensive and causes adverse effects. Medicinal plants
or bioactive compounds are rich source of antioxidant and such property shows role in
diseases cure and prevention. The concentration of myricetin content varies significantly
(10–1600 mg/kg) between different plants and vegetables. Myricetin is a flavonoid and its
role in health management have been confirmed as hepatoprotective, anti-inflammatory,
neuroprotective and cardioprotective. Moreover, its role in cancer prevention has been
proven as it suppresses the cancer growth, inhibit angiogenesis, regulate cell cycle, inhibit
inflammation, induces apoptosis and modulates various other cell-signalling molecules.
The myricetin used in different cancer cell lines significantly varies (5–200
µ
M) to evaluate
its anticancer potential. Nano based formulation has been prepared and their role in cancer
inhibition tested and result confirms that these formulations can be employed as delivery
to improve the bioavailability of this compound. However, different challenges should be
focused on engineering different nanoformulations of myricetin to overcome its poor bio-
availability, loading capacity, targeted orientation and premature release of this compound.
Furthermore, some derivatives of myricetin need to be synthesized to check their anticancer
potential. Besides, synergistic effects with anti-cancer drugs have been proven through
increased the induction of apoptosis and reduced the cell viability. To identify the precise
effectiveness of this novel compound in preventing and treating cancer, extensive future
studies based on in vivo or clinical studies are indeed recommended.
Author Contributions:
Conceptualization, A.H.R., A.A., K.S.A., A.A.K., S.A.A., W.M.A. and B.F.A.;
methodology, F.A., W.M.A. and B.F.A.; formal analysis, A.H.R., A.A., K.S.A. and A.A.K.; investigation,
S.A.A. and F.A.; resources, A.A., S.A.A. and A.H.R.; writing—original draft preparation, A.H.R.;
writing—review and editing, A.H.R., A.A., K.S.A., A.A.K., S.A.A., W.M.A. and B.F.A. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interests.
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