1. Introduction
Cancer is an extremely complex disease characterized
by the unregulated growth of cells, mostly due to deregulation of
the cell cycle. The cell cycle is a tightly regulated and highly
controlled process that depends on cyclins, cyclin-dependent
kinases (CDKs) and the inhibitors, p21 and p27. For the cell to
divide correctly, all regulatory molecules must function properly
as any imbalance between these regulatory molecules may induce a
state of tumorigenesis (1). The
majority, if not all, cancers exhibit mutations or the
overexpression of cyclins and CDKs, resulting in unrestricted
proliferation. The entire cell cycle is a promising therapeutic
target (2). By stalling cells at key
checkpoint transition points in the cell cycle, such as at G0/G1 or
G2/M, tumor cells can be prevented from completing mitosis, leading
to growth inhibition and apoptosis (3). A number of natural compounds have been
found to manipulate the cell cycle. One such effective chemical
compound is emodin, which is an anthraquinone derived from several
plants used in traditional medicine (4).
Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has
a planar aromatic structure that accounts for its interaction with
a range of molecular targets. It is mainly extracted from medicinal
plants, such as Rheum palmatum (rhubarb), Polygonum
cuspidatum and Aloe vera, which have been traditionally
used for centuries in Chinese and Indian Ayurvedic medicine
(4). Traditionally,
emodin-containing herbal products have been used as laxatives,
anti-inflammatory agents, antimicrobials and liver protectants,
suggesting its wide-ranging pharmacological potential beyond cancer
therapy (5). Chemically, emodin has
a low water solubility and moderate lipophilicity, which affect its
bioavailability and metabolism in vivo, presenting a
potential barrier to its therapeutic use (6). However, emodin has gained considerable
interest for its multifunctional biological effects, which include
antioxidant and pro-oxidant activities, the regulation of
apoptosis, anti-angiogenic activity and the modulation of various
signaling pathways, including PI3K/Akt, MAPK and NF-κB (6).
In terms of anticancer activity, emodin is
effective, as it can regulate specific proteins involved in the
cell cycle, inhibit threshold proliferation for tumors and induce
apoptosis. Emodin increases CDK inhibitors (CDKIs), such as p21 and
p27, that inhibit CDK activity and halt cell cycle progression
altogether (7). Emodin also acts on
a number of other signaling pathways which play a key role in the
growth of cancer cells, rendering it a promising candidate for
targeted cancer therapy (8). The
present review discusses the mechanisms by which emodin induces
cell cycle arrest, with a focus on its regulation of cyclins, CDKs
and checkpoint pathways. The present review also addresses the
effects of emodin on blocking the G0/G1 and G2/M phases of the cell
cycle and its impact on tumor proliferation, thereby evaluating its
efficacy as an anticancer agent and role in interrupting abnormal
cell cycle progression.
2. Mechanisms of cell cycle regulation in
cancer
The cell cycle is a process that regulates cell
growth, DNA duplication, and ultimately, the division of cells into
daughter cells. The cell cycle has five phases, which include G0
(resting phase), G1 (pre-DNA synthesis phase), S (DNA synthesis
phase), G2 (pre-mitotic phase) and M (mitosis). The different cell
cycle phases are tightly regulated by a network of regulatory
proteins, but largely cyclins and CDKs. Cyclins are phase-specific
activators that manage the passage of appropriate CDKs through the
cell cycle by binding and activating CDKs. CDKIs help regulate the
progression of the cell cycle, similar to that of a checkpoint, to
limit uncontrolled division and errors of division (9).
In normal cells, controlled cell proliferation is
maintained and regulated by the appropriate levels of cyclins, CDKs
and CKIs. Nonetheless, the regulation of cyclin, CDK and CKIs in
cancer is altered from normal levels due to genetic mutations and
epigenetic changes. Genetic changes, including cyclins being
overexpressed, the loss of CDKIs (p21 and p27) and mutations of
tumor suppressor genes (p53 and Rb), cause the lack
of regulated DNA duplication and cell division required for tumor
growth (10). In addition to
overactivation and genetic mutation, there is aberrant regulation
at the transition from the G1 to the S phase of the cell cycle, and
the G2 to M phase of the cell cycle, which can allow cancer cells
to resist cell cycle arrest, accumulate DNA damage and proliferate
in an uncontrolled manner (11).
Genomic instability driven by dysregulation of the
cell cycle is a central hallmark of cancer that facilitates tumor
evolution and therapeutic resistance. Uncontrolled cell division
enables cancer cells to accumulate genetic alterations that promote
survival, invasion and metastasis (12). In this context, targeting key
regulators of the cell cycle, including cyclins, CDKs and
checkpoint proteins has emerged as an effective therapeutic
strategy. Natural products have gained attention as promising
sources of such modulators, with compounds such as emodin
demonstrating the ability to induce cell cycle arrest through
multiple regulatory pathways (13).
Understanding how emodin interacts with these critical regulators
requires a detailed appreciation of the underlying molecular
signaling mechanisms governing cell cycle progression.
The cell cycle is regulated at the molecular level
by phosphorylation-dependent pathways. Cyclin-CDK complexes control
the cell cycle by the phosphorylation of substrates, including the
retinoblastoma (Rb) protein, resulting in E2F transcription factor
release (14) and subsequent S-phase
gene activation. In response to DNA damage and stress, tumor
suppressors, including p53, lead to the induction of CDKIs (such as
p21), resulting in cell cycle arrest (15). The disruption of these interconnected
pathways underpins the uncontrolled growth of cancer cells and
represents key targets for therapy. The following section discusses
in detail how emodin influences these molecular mechanisms to
induce cell cycle arrest in cancer cells.
3. Emodin-induced cell cycle arrest
Rather than exclusively modulating gene expression,
emodin regulates phosphorylation-based regulatory networks, such as
cyclin-CDK complexes, checkpoint kinases and tumor suppressors. By
the combined effects of these mechanisms, emodin blocks key cell
cycle transitions, such as the G1/S and G2/M checkpoints, to induce
persistent cell cycle arrest and suppress tumor cell growth
(Fig. 1) (16). Crucially, these actions are
context-dependent and vary between cancer types due to their
different genetic and signaling landscape.
Primary molecular targets and upstream
mechanisms of emodin
While the downstream consequences of emodin on
cyclins, CDKs and checkpoint proteins are well documented, the
primary targets of emodin remain under investigation. Available
evidence indicates that emodin does not have a single main target,
but rather displays multiple upstream pleiotropic effects (17). One of the most extensively studied
mechanisms is the generation of cellular reactive oxygen species
(ROS), which result in oxidative stress and DNA damage, activating
the ATM/ATR pathway. This leads to the phosphorylation of
downstream checkpoint kinases (Chk1 and 2) it's the stabilization
of p53, resulting in cell cycle arrest (17,18).
Beyond its effects on ROS-dependent signaling, emodin has been
demonstrated to affect key growth and survival pathways, such as
PI3K/Akt and MAPK, which affect upstream regulators of cyclin
expression and cell cycle progression (19). Moreover, recent studies indicate that
emodin may disrupt redox regulatory proteins such as MTH1,
promoting increased oxidative DNA damage in cancer cells (20,21). The
planar anthraquinone structure of emodin has also been shown to
potentially interact with DNA or topoisomerase, potentially causing
replication stress and checkpoint activation, although these
interactions are less well understood (22). Taken together, these findings suggest
that emodin functions as a multi-faceted agent that triggers
upstream stress and signaling responses, which ultimately converge
on the classical cell cycle regulatory pathways described in
subsequent sections.
Regulation of cyclins and CDKs
Cyclins are key proteins that progress the cell
cycle through CDKs by forming complexes. It has been demonstrated
that emodin alters the expression of several cyclins, leading to
cell cycle arrest at checkpoints (23). Cyclin D and cyclin E facilitate the
transition of cells from the G1 to the S phase, and emodin has been
shown to downgrade their expression to limit DNA synthesis and help
limit tumor cell proliferation (16). Additionally, the downregulation of
cyclin A and cyclin B helps regulate the S and G2/M transition,
which results in the additional blockade of the cell cycle, mitotic
progression and limitation of tumor growth. CDKs, namely CDK2, CDK4
and CDK6 are key regulators of cyclin activity, and are often
overexpressed in several forms of cancer (24). Emodin has been shown to inhibit the
activity of these kinases, preventing them from interacting with
their cyclins, thereby arresting progression through the cell cycle
(25). Moreover, these kinases
regulate the phosphorylation of the Rb protein, which is crucial
for cell progression, keeping the cells from entering a
proliferating state, thus forcing the cells into quiescence or
arrest (26). The loss of CDK
activity ultimately leads to growth suppression and the increased
susceptibility of cancer cells to apoptosis.
CDKIs, such as p21 (Cip1/Waf1) and p27 (Kip1),
function as tumor suppressors by negatively regulating CDK and
enforcing cell cycle checkpoints. Emodin modulates the expression
of those inhibitors to further inhibit CDKs 2 and 4, in addition to
its direct impact on the kinases themselves (27). The elevated levels of CKIs further
induce a cellular arrest in the G0/G1 phase of the cell cycle,
preventing cells from entering into the S phase. Notably, p21 has
also been demonstrated to inhibit CDK activity in a p53-independent
manner, permitting emodin to maintain its effects against cancer
cells even in tumors lacking functional p53 signaling (28). By simultaneously modulating the
functions of cyclins, CDKs, and CKIs, emodin disrupts the cancer
cell cycle, inhibits cancer cell proliferation and promotes
dormancy (Table I) (29).
 | Table IKey cell cycle proteins modulated by
emodin. |
Table I
Key cell cycle proteins modulated by
emodin.
| Protein | Effect | Functional
consequence | Cancer model | Authors, year of
publication (Refs.) |
|---|
| Cyclin D1 | ↓ | Reduced G1
progression; proteasomal degradation ↑ | Breast cancer
(MCF-7); hepatocellular carcinoma | Sui et al,
2014(35); Subramaniam et al,
2013(67) |
| Cyclin E | ↓ | Inhibited S-phase
entry; CDK2 partner lost | Colorectal cancer
(HCT116); gastric cancer | Li et al,
2022(7); Liu et al,
2023(8) |
| CDK2 | ↓ | Reduced kinase
activity; Rb Ser811 not phosphorylated | Breast cancer
(MCF-7); cervical cancer (HeLa) | Hsu and Chung
2012(28); Lande et al,
2023(45) |
| CDK4 | ↓ | Impaired Rb
Ser780/795 phosphorylation; G1 arrest | Hepatocellular
carcinoma (HepG2); breast cancer | Subramaniam et
al, 2013; (67); Sui et
al, 2014(35) |
| CDK6 | ↓ | Cyclin D1-CDK6
complex lost; G1 checkpoint enforced | Multiple cancer
types | Vermeulen et
al, 2003(26); Liu et al,
2023(8) |
| p21
(Cip1/Waf1) | ↑ | CDK2/CDK4
active-site blockade; p53-dependent and -independent | Cervical cancer
(HeLa); lung cancer (NSCLC, A549) | Lande et al,
2023(45); Wahi et al,
2021(20) |
| Cyclin D1 | ↓ | MCF-7 inactivation;
MDA-MB-231 migration blocked | Breast cancer;
colon cancer cells | Okon et al,
2023(69) |
| CDK2/Cyclin
B1/ERCC1/AKT | ↓ | DNA damage; γH2AX
foci; p53 stabilization | Multiple cancer
types | Akkol et al,
2021(49) |
G0/G1 phase arrest
The G0/G1 phase represents a bottleneck in the cell
cycle where cells commit to initiating the replication process of
their genome or enter a quiescent state. Cancer cells avoid proper
regulation of the G1-S transition to undergo unwarranted and
uncontrolled division processes (30). Emodin has been reported to induce
G0/G1 arrest by disrupting regulatory proteins that control cell
cycle checkpoints, which ultimately halts tumor growth and improves
the therapeutic potential of anticancer treatments (31). The mechanism of action of emodin on
G0/G1 arrest involves modulating cyclins, CDKs and tumor suppressor
pathways. Key drug-mediated actions involve the inhibition of the
cyclin D/CDK4 and cyclin E/CDK2 complexes, which help drive direct
the progression of cells through the G1 checkpoint (32). With decreased reliance on CDK
complexes, emodin diminishes the phosphorylation of the Rb
proteins, permitting transcription factor E2F to release cells to
enter S-phase. As a consequence, cells are left in the G0/G1 phase,
indefinitely delaying DNA replication.
Cyclin D and CDK4/CDK6 are complexed to regulate the
G1 phase transition, while cyclin E and CDK2 regulate the later G1
phase transition into S-phase (33).
The relevant cyclins are typically overexpressed in a wide array of
cancers, leading to high rates of proliferation (34). Emodin significantly reduces the
expression levels of Cyclin D and Cyclin E as well as their
respective CDKs (35). Since emodin
down-regulates CDK activity, there is less phosphorylation of the
Rb protein. This stalls the G1-S transition and can result in
arrest of the cancer cell. Further characterization of emodin
demonstrates that it increases the proteasomal degradation of
cyclin D1, increasing the effectiveness of halting cell
progression. Emodin arrests cells by blocking these relevant
regulatory complexes, assuring tumor cells do not progress to the
first checkpoint of the cell cycle and decreasing the ability of
cancer cells to proliferate (36).
Protein p53 is a major tumor suppressor that
regulates the G1 checkpoint, inducing the cell cycle in response to
damaged DNA or other stressors. Emodin has been shown to induce p53
activation (37), resulting in a
transcriptional upregulation of p21 (Cip1/Waf1) and p27 (Kip1)
(38), both of which are strong
CKIs. p21 and p27 have affinity to bind with CDK2 and CDK4 to
prevent them from binding to cyclins, which inhibits cell cycle
progression (39). Emodin-mediated
p53 activation can further serve to upregulate p21 expression,
reinforcing its effect on CDK inhibition and retaining G1 arrest.
It can also promote p21 expression in a p53-independent manner,
allowing treatments to be effective in p53-mutated cancers that are
inherently resistant to traditional therapies (40). Emodin can enforce G0/G1 arrest
through concurrent downregulation of cyclins/CDKs and upregulation
of CKIs (Table I), leading to
decreased proliferation of cancer cells and increased cancer cell
sensitivity to apoptosis (41).
Overall, these data suggest that emodin is a promising therapeutic
agent in cancers linked to defects in cell cycle control.
G2/M phase arrest
The G2/M checkpoint is a key regulatory checkpoint
in the cell cycle to ensure that cells do not continue to mitosis
with damaged or unreplicated DNA. Emodin has been shown to cause
G2/M phase arrest in a number of cancer cells, effectively halting
their proliferation and inducing prior steps along apoptotic
pathways (42). G2/M arrest likely
occurs due to the downregulation of the cyclin B/CDK1 complex, the
activation of checkpoint kinases (Chk1/Chk2), and other steps that
are interfering with mitotic progression (43). The cyclin B/CDK1 complex is critical
in regulating entry into mitosis, and cancer cells frequently
dysregulate this process, resulting in uncontrolled proliferation
(44). Emodin reduces the expression
of cyclin B1, and also inhibits the activity of CDK1, stopping
cells from moving from the G2 phase into mitosis (45). Emodin has been shown to decrease the
phosphorylation of CDK, required for its activation, and to
contribute to G2 arrest for a prolonged duration (46).
Furthermore, in addition to inhibiting cyclin
B/CDK1, emodin also interferes with mitotic spindle formation,
leading to abnormal chromosome segregation (46,47).
This results in a lengthened duration of mitotic arrest, which
eventually leads to mitotic catastrophe and apoptotic cell death.
Emodin induces DNA damage, activating the ATM/ATR signaling
pathways, confirming G2 arrest (48). Given the accumulation of DNA damage
and stalled replication forks, the cell is warned of the genetic
instability and subsequently stops in mitosis, not allowing
unstable and damaged cells to divide. Chk1 and Chk2 are two major
checkpoint kinases that sense DNA damage and replication stress.
Emodin has been reported to trigger the activation of Chk1/2,
leading to the phosphorylation of Cdc25C, a key phosphatase in CDK1
activation (49). When Cdc25C is
phosphorylated, it is retained in the cytosol, making it unable to
induce mitotic entry. In addition to Cdc25C retention, Chk1/Chk2
ensures p53 stabilization, a key tumor suppressor, which leads to
additional transcription of p21 and GADD45 to maintain G2/M arrest
(50). Through these mechanisms,
emodin is able to cease tumor cell proliferation and is a promising
agent to impact anticancer therapies through cell cycle regulation
(Table II).
| Table IISummary of emodin-induced cell cycle
arrest across cancer models. |
Table II
Summary of emodin-induced cell cycle
arrest across cancer models.
| Cancer type | Cell
line/model | Phase arrest | Key
targets/pathways | Conc.a | Clinical
relevance | Authors, year of
publication (Refs.) |
|---|
| Hepatocellular
carcinoma | HepaRG; HepG2 | S and
G2/Mb | Cyclin A/CDK2
inhibition; MAPK/P13K/AKT | 20-60 µM | Inhibited HepaRG
proliferation; induced cell cycle arrest and apoptosis through the
ROS- mediated mitochondrial pathway | Dong et al,
2018(77); Yin et al,
2022(83) |
| Colorectal
cancer | HCT116; SW480 | G1/Sc | CDK1/CDK2 down-
regulation; Rb inhibition | 30-80 µM | Suppresses cell
proliferation; inhibits tumor growth in xenograft model | Li et al,
2022(7) |
| Breast cancer | MCF-7
(ER+); MDA-MB-231 (TNBC) | G0/G1b |
ERα–MAPK/Akt-Cyclin D1/Bcl-2
pathway; p53- dependent arrest; CD155 downregulation | 20-75 µM | TNBC subtypes
sensitive; p53 status predictive of response | Sui et al,
2014(35); Fang et al,
2019(29) |
| Lung cancer | A549 (NSCLC) | G0/G1b | MTH1 inhibition;
ROS augmentation; colony formation inhibition; senescence-like
state induced | 20-60 µM | Cisplatin
sensitization; combination therapy potential; radiosensitization
reported | Wahi et al,
2021(20); Zhang et al,
2022(78) |
| Pancreatic
cancer | PANC-1; BxPC-3 | G0/G1
(limited)d | Partial CDK4
suppression; p16/RASSF1A demethylation synergy with
5-Aza-CdR | 40-100 µM | Resistance via KRAS
pathway; requires delivery optimization | Pan et al,
2016(88); McDonald et al,
2022 (97) |
| Glioblastoma
(GBM) | LN18/LN428,
U87 | G2/M
(partial)d | Boosts neutron
induced apoptosis; AhR signaling pathway | 50-120 µM | Combined therapy
promoted PARP1 fragmentation and caspase-3 expression; inhibits the
migration of glioblastoma | Kim et al,
2022(52); Xu et al,
2022(93) |
Nonetheless, questions remain regarding potential
toxicity to normal cells and the necessity for accurate dosing
strategies to increase efficacy while decreasing side effects.
Although emodin has demonstrated activity across multiple cancer
models, its impact depends on cancer type, genetic mutations, and
the tumor microenvironment. Emodin monotherapy has demonstrated
partial potential in pancreatic cancer (51) and glioblastoma (52) (Table
II), which may be due to inherent mechanisms of resistance,
efflux of the drug, or other compensatory survival mechanisms.
Although the efficacy of adding the chemotherapy agent,
5-fluorouracil, has been documented in vitro and in
vivo (53-55),
there is no uniformity of its effectiveness depending on cancer
type, bioavailability issues and toxicity (56). Targeted delivery systems, combination
therapy and mechanisms need to be incorporated in future research
to maximize the capacity for emodin as a therapeutic in cancer.
4. Impact on tumor cell proliferation
The ability of emodin to modulate the cell cycle has
implications for tumor suppression, mostly through inducing cell
cycle arrest, blocking proliferation, and promoting both apoptosis
and cell death pathways. In numerous studies (57-61),
emodin has shown promise for anticancer potential. However,
variations in response across tumor types and pharmacokinetic
limitations highlight the need for additional studies (62).
In vitro efficacy
Emodin has been shown to inhibit cell proliferation
in a number of in vitro cancer studies, including in breast,
lung, liver, colorectal and prostate cancers (63-66).
The emodin- mediated suppression of cell proliferation can result
in G0/G1 or G2/M arrest, arrest in mitosis and can trigger
apoptosis (Fig. 2).
 | Figure 2Emodin exerts potent
anti-proliferative effects across multiple cancer types by
disrupting key regulators of the cell cycle and survival pathways.
It induces cell cycle arrest at G0/G1 and G2/M phases, suppresses
mitotic progression, and promotes apoptosis through modulation of
proteins, such as cyclin D1, Bcl-2, and the Cyclin B/CDK1 complex.
These molecular effects are particularly evident in hepatocellular
and colorectal cancer models, leading to impaired cell cycle
progression and increased cell death. Additionally, emodin reduces
colony formation and induces a senescence-like state in highly
proliferative cancers, including breast, lung, liver and prostate
cancers. |
In hepatocellular carcinoma cells, emodin has been
reported to suppress Cyclin D1 and Bcl-2, causing a significant
reduction in the cell cycle (67).
Likewise, emodin also suppresses the migration and growth of the
colorectal cancer cell lines (SW480 and SW620) by inhibiting the
Wnt signaling pathway, and downregulating related genes and
proteins, such as β-catenin, and Cyclin D1(68). The impact on cell cycle, and growth,
is even more evident in cancers with very high mitotic indices,
such as aggressive breast and lung cancers, which has shown a great
reduction in colony formation and induction of a senescence-like
state (69). However, not all
cancers are equally sensitive to emodin. It has been found that
cancer cells with functional p53 are more sensitive to emodin
treatment, while cancer cells lacking p53 are relatively resistant
to emodin-induced arrest (70).
These results indicate that the effect of emodin is highly
dependent on the genetic background of the tumor.
In vivo tumor suppression
In vivo studies using tumor xenograft models
have also demonstrated the anticancer effects of emodin (71,72).
Emodin-treated tumors exhibit slower growth, increased apoptosis
and lower proliferative indices. However, the effects are generally
less pronounced than in vitro, due in part to poor
pharmacokinetics, such as low bioavailability and rapid clearance
(73,74). These results highlight the challenges
of translating in vitro success to in vivo
efficacy.
Synergistic effects with chemotherapy
and radiotherapy
Emodin has also been investigated as a
chemosensitizer (chemotherapy) and a radiosensitizer (radiation) to
improve the efficacy of conventional cancer therapies. It has
demonstrated additive or synergistic effects with doxorubicin,
cisplatin and paclitaxel, increasing cancer cell sensitivity to
drug-induced cell death (75,76).
This may be partly related to the ability of emodin to inhibit DNA
repair and induce oxidative stress, rendering cancer cells more
vulnerable to damage from chemotherapy. Emodin has also been shown
to increase radiosensitivity by blocking DNA repair processes and
increased ROS production (77).
Pre-clinical studies have demonstrated an enhanced tumor
suppression when emodin is used as an adjuvant to radiation therapy
in lung and cervical cancer models (78,79).
These results indicate that emodin could be used as an adjuvant
therapy in cancer treatment.
5. Emodin and the regulation of non-coding
RNAs
Recent investigations have indicated that emodin
regulates non-coding RNAs, such as microRNAs (miRNAs/miRs) and long
non-coding RNAs (lncRNAs), that have been shown to play a role in
the cell cycle (80,81). For instance, miR-34a is a known tumor
suppressor that upregulates p21, an inhibitor of CDKs, while miR-21
is an oncogenic miRNA whose targets include tumor suppressors such
as PTEN (82,83). There is evidence to indicate that
emodin can increase miR-34a and decrease miR-21 expression to
further inhibit CDK activity and induce cell cycle arrest (84). In addition, oncogenic lncRNAs such as
MALAT1, which is upregulated in aggressive cancers, promote cyclin
expression and the cell cycle. Thus, based on the accumulating
evidence of the targeting of the MALAT1 by small molecules
(85), it would be interesting to
assess the potential of emodin to modulate the stability and
function of MALAT1 in cancer cells.
6. Epigenetics and cell cycle arrest
In addition to its epigenetic regulation of the cell
cycle, emodin exhibits direct kinase inhibition. Histone
acetylation and methylation play a pivotal role in modulating the
expression of key cell cycle regulators, including the crucial
CDKIs p16INK4A and p21. Emodin has demonstrated the ability to
modulate histone deacetylases, resulting in increased histone
acetylation and manipulation of tumor suppressor gene expression
that mediates G1/S arrest (86,87). The
re-activation of tumor suppressors and re-establishment of RB
pathway control that prevent uncontrolled proliferation are
influenced by DNA methylation. Emodin can regulate the
reactivation, particularly at the p16INK4A locus (88). Emodin also blocks the activity of
EZH2 chromatin remodeling enzymes, which silence tumor suppressor
genes by trimethylating H3K27, further confirming its ability to
induce cell cycle arrest (89,90).
7. Emodin in alternative cell cycle
models
While it is known that emodin can lead to G1 and
G2/M cell cycle arrest (91),
further studies are required to investigate whether emodin can also
induce other forms of cell cycle arrest, such as polyploidy and
mitotic catastrophe. Certain natural products can induce
endoreduplication, rendering cells polyploid and can ultimately
trigger apoptosis or permanent cell cycle arrest (92). If emodin prevents mitotic spindle
assembly, it may induce mitotic catastrophe (47), as in the case of rapidly dividing
cancers, such as glioblastoma (93),
and pancreatic cancer (94).
Differentiating between cell quiescence and cell cycle arrest is
important for therapeutic outcomes. The majority of
chemotherapeutic agents induce G0 quiescence, which can be reversed
and resumed upon drug removal. However, if emodin induces an
irreversible senescent-like state, this would be a more sustained
antitumor effect (95). Further
research is required to establish whether the effects of emodin are
reversible or induce irreversible cell cycle arrest (96).
8. Therapeutic implications
Emodin may be used as an adjuvant and single agent
against cancer, particularly as it induces cell cycle arrest and
high levels of sensitization to chemotherapy/radiation (78). Such multifaceted actions indicate
that emodin functions as a pleiotropic bioactive agent, which can
modulate various biological and pathological processes, thereby
providing a broader perspective of its use in cancer treatment
(25).
Improving bioavailability
However, despite its potent anticancer properties,
the therapeutic use of emodin is limited by its low water
solubility, high metabolic rate and low systemic availability
(97). To address these challenges,
novel drug delivery strategies have been explored and tested in
preclinical studies. Nanoparticles, such as polymeric nanoparticles
and lipid-based nanoparticles have shown improved pharmacokinetics,
selective tumor accumulation and higher intracellular drug
concentrations (31). Liposomal
formulations of emodin have also been reported to enhance its
stability, decrease its systemic toxicity and enable controlled
release of the drug in tumors (98,99).
Moreover, nanoemulsions and solid lipid nanoparticles have been
investigated to improve the solubility and permeability of emodin,
leading to improved in vivo efficacy (100,101).
These nanocarriers not only shield emodin from premature
degradation, but also facilitate passive or active targeting of
tumors through enhanced permeability and retention (EPR) mechanisms
(102). These promising results in
xenografts and other preclinical models have generated continuing
research on these specific nanocarrier systems and quantitative
therapeutic benefits (100,103).
Several pre-clinical studies have subsequently
provided quantitative proof of the efficacy of nanocarrier-based
emodin delivery systems (31).
PEGylated liposomal emodin formulations, for instance, exhibit
prolonged circulation time and improve tumor accumulation in
xenograft mouse models than free emodin, leading to a significantly
higher suppression of tumor growth with less systemic toxicity
(104,105). Likewise, polymeric lipid
nanoparticles loaded with emodin were found to enhance its oral
bioavailability and cellular uptake and therefore, apoptotic
activity was increased in hepatocellular carcinoma models (106). It has also been shown that
polymeric nanoparticles based on poly(lactic-co-glycolic acid)
possess sustained drug release property and enhanced intracellular
retention resulting in increased antiproliferative activity of
emodin in breast and hepatocellular carcinoma cells (107,108).
In another method, nanoemulsion based formulation enhanced the
aqueous solubility and permeability, resulting in higher in
vivo antitumor activity and pharmacokinetic stability (109,110).
Overall, these results suggest that the nanocarrier system can
significantly counteract the inherent pharmacological limitations
of emodin and enhance its translational potential in cancer
therapy.
Structural modifications and
derivatives of emodin
The structural modification of emodin is another
promising avenue with which to improve its therapeutic efficacy.
Derivatives with modified structures, such as glycosylated
compounds (e.g., emodin-8-O-β-D-glucoside) have shown enhanced
solubility, stability and anticancer efficacy compared with the
parent compound (7). Furthermore,
the development of new emodin analogs seeks to improve
pharmacokinetics, while retaining or boosting biological activity.
Prodrug strategies have also been explored to enhance absorption
and selectivity (110,111). Such modifications can increase cell
membrane penetration, decrease enzymatic degradation, and increase
plasma half-life. Overall, these types of structural modifications
play a crucial role in addressing the drug development challenges
of emodin to facilitate its clinical development.
Clinical translation and current
gaps
Although emodin has shown promising anticancer
activity in preclinical studies, it has yet to be fully developed
for clinical use. Currently, there are no reported clinical trials
testing emodin as a single agent for cancer treatment. This
underscores the need for effective translation of in vitro
and in vivo results to clinical application. The lack of
clinical evidence may be due to issues surrounding its
bioavailability, pharmacokinetics and toxicity at higher doses
(97). However, emodin is still
being explored in combination treatments and as a scaffold for the
development of more potent analogues. Future studies are required
to focus on conducting proper preclinical studies with improved
formulations, followed by well-conducted clinical trials to
determine safety, efficacy and effective dose in humans. Overcoming
these challenges is crucial to harnessing the full therapeutic
potential of emodin in cancer treatment.
Safety profile and comparison with
conventional chemotherapy
While emodin has shown potential in cancer
treatment, preclinical research has suggested that it may display
dose-related toxicity, such as liver toxicity and gastrointestinal
irritation, likely due to its pro-oxidant effect and metabolic
instability (36). Furthermore,
emodin has also been shown to trigger oxidative stress in normal
cells at higher doses, which could limit its therapeutic index and
lead to potential side-effects (112). Nevertheless, emodin has several
advantages over classical chemotherapeutics, such as doxorubicin,
cisplatin and paclitaxel. Conventional chemotherapy agents are
frequently accompanied by severe side-effects, including
myelosuppression, cardiotoxicity, neurotoxicity and multidrug
resistance (80). However, emodin,
being a natural product, displays a relatively selective
cytotoxicity against cancer cells in a number of preclinical
studies, owing to its ability to target cancer-specific
vulnerabilities, such as elevated ROS levels and altered signaling
pathways (8,49). Additionally, its ability to target
multiple pathways also diminishes the potential for resistance
development observed with single-target chemotherapies. While some
studies and reviews have explored the potential for clinical use,
these are largely speculative, and there is a clear gap between
experimental findings and clinical development (6,25,78,80,100).
Thus, comprehensive pharmacokinetic evaluations, toxicity
assessments and early clinical studies are crucial to confirm the
safety and efficacy of emodin-based treatments in humans.
9. Conclusion and future directions
Emodin has clocked into the potential of being a
very effective natural agent that has an anticancer effect,
particularly when causing cell cycle arrest and the contraction of
tumors. Emodin blocks the uncontrolled growth of cancer cells by
affecting important regulators of the G0/G1 and G2/M stages,
including cyclins, CDK, p21, p27 and checkpoint kinases (Chk1/Chk2)
(38,110). More recent studies have indicated
that emodin also regulates non-coding RNAs, including miRNAs and
lncRNAs, epigenetic modifications and alternative cell cycle
pathways (81). These are all
critical, yet currently unexplored pathways that may amplify its
anticancer properties. The capacity of emodin to regulate miRNAs,
such as miR-34a and miR-21, modify DNA methylation and histone
acetylation, and cause polyploidy or mitotic catastrophe, render it
a versatile cancer therapy method.
Some identifiable challenges have prevented this
current bench research from being translated into clinical use,
despite the potential. Emodin has limited bioavailability, is
rapidly metabolized and has poor solubility. Nanoparticle delivery
systems, structural modifications and newer formulations may help
improve its limitations, and may lead to more effective therapies.
Future studies are warranted to evaluate the safety and efficacy of
emodin for humans through well-designed preclinical and clinical
studies. Investigating its potential synergistic effect with
chemotherapeutics, immunotherapy and/or targeted therapy also
warrants further evaluation. By addressing present limitations and
fully utilizing its numerous mechanisms of action (e.g., cell-cycle
arrest, epigenetic effects and/or modulating non-coding RNAs),
emodin may emerge as a critical component of modern anticancer
therapeutics.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
AGB and LK conceptualized the study. SD, JK and KL
were involved in literature search. KL, SP and RN were involved in
preparing the first draft of the manuscript. SD, JK, KL and SP were
involved in the writing and preparation of the original draft of
the manuscript. SK, AG and LK were involved in the writing, review
and editing of the manuscript. AGB and LK supervised the study. All
authors have read and approved the final manuscript. Data
authentication is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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