Introduction
Curcumin is a natural β-diketone polyphenolic
compound extracted from the rhizome of Curcuma longa and
other plants, such as Curcuma zedoaria and Curcuma
aromatica Salisb. (1,2). Previous research has demonstrated
that curcumin presents a variety of biological properties, such as
anti-inflammatory (3,4) and antitumor effects (5,6),
neuroprotection during surgery (7), depression and anxiety relief
(8,9) and antiviral and antibacterial effects
(10,11). Cancer, chronic inflammation,
depression, anxiety and nerve damage are complex diseases that
afflict patients and present challenges for medical workers;
therefore, researchers aim to identify effective compounds in the
treatment and relief of these diseases. Curcumin is considered one
such potential compound; however, a limitation is that curcumin is
poorly soluble in water, unstable and has a low bioavailability
(12–16). Therefore, to improve the
pharmacological properties of curcumin, scientists have aimed to
design and synthesize new molecular structures of curcumin
(9,17–19).
Consequently, the molecular structures of curcumin have been
optimized through structural modification or hybridization, which
has resulted in different curcumin derivatives or analogs that have
beneficial modified physicochemical properties and improved
pharmacological activities compared to that of curcumin.
By optimizing the dosage form of curcumin and
generating emulsions, liposomes and polymer micelles, the
solubility of curcumin derivatives has been improved. Furthermore,
in order to improve the bioavailability of curcumin, curcumin and
its derivatives have been encapsulated and delivered in an indirect
manner based on nanoparticles and microemulsions (5,15).
Curcumin analogs also have the capacity to chelate metal ions and
may act as metal-chelating agent for pharmaceutical applications
(20). The present review mainly
summarizes the chemical structures and modification of curcumin and
its derivatives/analogs, as well as their molecular mechanisms in
cancer treatment.
Chemical structures and physicochemical
properties of curcumin
Curcumin is extracted from the rhizome of Curcuma
longa, Curcuma aromatica and Acorus of the Araceae
family (1,2), and is a natural polyphenolic compound
containing two β-keto groups. Curcumin is a yellow crystal with a
melting point of 183°C and its molecular formula is
C21H20O6. The primary structure of
curcumin is a 1,7-diarylheptane skeleton, containing two β-keto
moieties and two O-methylated phenols (21,22).
The presence of two phenolic hydroxyl groups at the ends of the
molecular structure makes it prone to conjugation under alkaline
conditions, resulting in keto-enol tautomerism (23) (Fig.
1).
In an alkaline environment, curcumin primarily
exists stably in its enol form and is reddish brown in color. In
acidic and neutral environments, the structure of curcumin changes
to the ketone form, which appears luminous yellow (23). These features make curcumin a
chemical acid-base indicator. Natural curcumin, due to its long
unsaturated aliphatic chain and benzene ring structure, is
insoluble in water at room temperature, but is soluble in alcohol,
acetone and other organic or alkaline solvents. In an acidic
environment, natural curcumin is stable (24). The characteristic yellow color of
turmeric is due to the presence of curcuminoids; of the components
in curcuminoids, besides curcumin, there are demethoxycurcumin,
bisdemethoxycurcumin and cyclocurcumin (Fig. 2A-C). Curcumin is the main bioactive
ingredient of turmeric, containing 3–5% of the total composition
(25).
In total, two natural curcumin derivatives,
demethylcurcumin and bisdemethylcurcumin, exist in nature, which
are also the two main forms of curcumin metabolized in the body
(26). Demethylcurcumin is a
diketone compound containing three phenolic hydroxyl groups, based
on the structure of curcumin, where the methyl group bonded to
hydroxyl oxygen at one end of the aryl ring is replaced by hydrogen
(Fig. 3A). Bisdemethylcurcumin is
also a diketone compound containing four phenolic hydroxyl groups
on the basis of the structure of curcumin, where both methyl groups
on the hydroxyl oxygens on the two aryl rings are replaced by
hydrogens (Fig. 3B).
The physiological function of curcumin predominantly
depends on the structure of phenolic hydroxyl groups and diketo
moieties. Phenolic hydroxyl groups are prone to chemical reactions
with active oxygen and free radicals, and are oxidized into keto
groups. Furthermore, curcumin can scavenge reactive oxygen species
(ROS) generated either in the mitochondria, by substance metabolism
or in response to environmental factors, and exhibits antioxidant
and anti-inflammatory activities (3,4).
Curcumin also reacts easily with strong electron-absorbing groups
and produces ROS, which exerts a toxic effect on tumor cells. It
has been shown that the substituent groups on the 4′ carbon atom of
the acyl ring of curcumin are the key to its pharmacological
activity (27). If large groups
that cannot form hydrogen bonds are introduced to the 4′ carbon
atom of the acyl ring, the pharmacological activity of curcumin is
decreased. However, the introduction of small groups, such as
hydroxyl (−OH), which can form hydrogen bonds to the 4′ carbon atom
of the acyl ring, can increase the biological activity of the
compound, but at the same time it may reduce selectivity (16,27).
Therefore, in order to obtain derivatives with optimal biological
activity and selectivity, it is necessary to select groups with
appropriate volume and hydrogen bond-forming ability.
Curcumin and curcuminoids have been commonly
researched due to their promising functional groups, such as
scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and
β'-hydroxyl-α,β-unsaturated ketone connected with acyl rings on
both sides. At present, the primary methods of structural
modification of curcumin and curcuminoids include: To increase or
decrease benzene substituents, change the length of fatty acid
chains, change the structure of diketones, substitute acyl rings
with heterocyclic rings or reduce unsaturated bonds or to hybridize
with other effective pharmaceutical structures.
Structural modification of curcumin and its
derivatives/analogs
Hydrogenated curcumin derivatives
Curcumin is metabolized rapidly and extensively in
both animals and humans. When administered orally, curcumin is
successively transformed to several reduced forms, including
tetrahydrocurcumin (THC), hexahydrocurcumin (HHC) and
octahydrocurcumin (OHC), in the liver as well as in the intestinal
mucosa, by phase I metabolism (Fig.
4). HHC is a major metabolite of curcumin, with lower levels of
octa-, tetra- and dihydro products being produced from curcumin
metabolism (27–29).
THC and OHC are common hydrogenation products of
curcumin. THC is formed by hydrogenation of double bonds on
aliphatic chains in the structure of curcumin. OHC is a product of
further hydrogenation of carbonyl oxygen to hydroxyl on THC.
Compared with curcumin, THC is more water soluble and more easily
absorbed by organisms, with advantages of increased water
solubility and chemical stability (30,31).
Due to the presence of a number of hydroxyl
substituents on these curcuminoids, the solubility and
bio-absorbability of the aforementioned compounds, such as THC, HHC
and OHC, are greater when compared with those of curcumin.
Furthermore, the change of a diketo structure to hydroxyl groups
reduces its cytotoxicity and enables the phenolic hydroxyl groups
to exert anti-inflammatory and antioxidant effects (32,33).
HHC has the same phenolic groups as the enol form of
curcumin; therefore, it presents with a number of the same
biological and pharmacological activities as curcumin. However,
since HHC has no olefinic double bonds, it is more stable than
curcumin at pH 7.4. Notably, HHC exhibits an increased chemical
stability and bioavailability compared with that of parent curcumin
in the treatment of Caco-2 human epithelial colorectal
adenocarcinoma cells (34,35). With enhanced pharmacological
activities, the use of hydrogenated curcumin derivatives may be
more promising as therapeutic drugs than that of curcumin.
The metabolites of curcumin have gained increasing
attention (30–33), the reason for which is that some
metabolites of curcumin, such as HHC and THC, have similar and
potentially improved bioactivities compared with that of curcumin.
The bioactive degradative products contribute to the
pharmacological effects of curcumin, which may suggest why natural
curcumin with poor oral bioavailability demonstrates efficacy in
in vivo studies (32–36).
Aryl-modified curcumin
derivatives
Acyl ring-modified substituents are a type of
curcumin derivative that were previously developed, and are
characterized by the original substituents on the acyl ring of
curcumin being either replaced with new substituents or with new
substituents added while keeping the original substituents
unchanged on the acyl ring. In a previous study, the phenolic
hydroxyl groups were replaced with halogens (Fig. 5), and it was found that its
photodynamic force (photodynamic inactivation, PDI) was raised with
the increase in halogen atomic number (9F,
17Cl and 35Br) (37). Curcumin produces cytotoxic ROS
through electron transfer and energy transfer stimulated with blue
light, which is known as the PDI. ROS can lead to different degrees
of damage to cell membrane structures, DNA, RNA and proteins;
therefore, halogenated curcuminoids have been testified to have
improved anticancer activity in 518A2 melanoma cells (37).
In other studies, the phenolic hydroxyl groups in
the aryl ring are protected by using reversible groups, so that
phenolic hydroxyl groups are not easily oxidized in the external
environment, and their stability, biological activity and
selectivity as drugs can be increased to a certain extent (38,39).
For example, Fang et al (38) replaced the methoxy group with
dimethylaminomethyl in order to introduce basic groups (Fig. 6). The introduction of basic groups
has been shown to make the curcumin derivative more easily soluble
in water and increase the steric hindrance of the molecule to
protect the active phenolic hydroxyl group. The substitution of
phenolic hydroxyl groups with different physiological activities
can improve the potential of penetrating the blood-brain barrier
and selectivity against certain types of cancer cells, such as in
liver cancer HepG2 cells, gastric cancer SGC-7901 cells, lung
cancer A549 cells and colorectal cancer HCT-116 cell lines
(38,40).
Numerous studies on curcumin derivatives have
focused on the modification of phenolic hydroxyl groups (38,39);
other studies have also utilized the chemical properties of the
phenolic hydroxyl group to make curcumin ether or ester (16,41).
The resulting derivatives of curcumin, AB1 and AB2, are more stable
than curcumin and exhibit enhanced solubility in water (16,41).
Recently, using novel galactosylated chitosan (GC)-modified
nanoparticles (GC@NPs), based on poly(ethylene glycol) methyl
ether-block-poly(lactide-co-glycolide), for drug loading of
curcumin has been shown to lead to superior inhibition of tumor
growth compared with that of free curcumin in hepatocellular
carcinoma. This finding demonstrates that GC@NPs may be a promising
curcumin nanocarrier for tumor therapy with a good biosafety
profile and high therapeutic efficacy (42).
Monocarbonyl-modified analogs
The diketo moiety of curcumin is prone to enol
tautomerism and unstable in terms of its chemical properties. In
order to overcome these defects, researchers have developed a
variety of monocarbonyl analogs of curcumin (MACs) (16), namely mono-ketone curcumin
(Fig. 7), which has a shorter
aliphatic chain connection compared with that of natural curcumin,
has increased water solubility and is more stable; it has been
experimentally demonstrated that shorter fat chains are associated
with increased water solubility and stability (43). Monocarbonyl-modified compounds are
mainly a combination of hydrogenated curcumin derivatives or
analogs, acyl ring substituent and diketone-modified derivatives
aforementioned, some of which exhibit certain anticancer, such as
in colon cancer, and antibacterial activities (44,45).
MACs have been shown to exhibit increased anticancer properties
compared with that of curcumin. In recent years, numerous studies
have emphasized the pharmaceutical significance of MACs as
effective anticancer agents in hepatocellular carcinoma and
colorectal cancer (46–48).
Bis-imino and bis-amino curcumin
derivatives
A novel set of curcumin analogs has been synthesized
from a bis-aldehyde derivative of hydroxybenzylidene cyclohexanone
and various alicyclic and aromatic amines, which include bis-amino
and bis-imino curcumin derivatives (Fig. 8A and B). A characteristic of
bis-amino and bis-imino curcumin derivatives is that they have a
Schiff base moiety (49).
Bis-imino and bis-amino curcuminoids have been tested for
anticancer activity against MCF7 human breast carcinoma cells, and
some of them, such as 3k, 3b and 3l, have been shown to exert more
potent anticancer activity in MCF-7 cells compared with that of
curcumin, as determined by MTT assay (49). The IC50 values of these
three compounds (3k, 3b and 3l) were <10 µg/ml, while
methotrexate and curcumin have IC50 values in the range
of 100–300 µg/ml.
Aliphatic chain-modified
substituents
The phenolic hydroxyl group in the acyl ring of
curcumin is an important pharmacophore, which can improve the water
solubility of curcumin derivatives, and the antioxidant activity
can be effectively increased when multiple phenolic hydroxyl groups
are present in the molecule (50).
The carbon-4 atom between β-diketone of curcumin can be linked to
various groups, such as 4-phenylaminomethyl curcumin, arylidene
curcumin and pyrazole curcumin, to form curcumin analogs (Fig. 9). As for these designed analogs,
the addition of more phenolic hydroxyl groups have been shown to
possess increased beneficial physicochemical and biological
activities, such as anti-inflammatory, antioxidant and
antibacterial activities via inhibition of cyclooxygenase in
vitro (50), which may be
applied in cancer treatment.
Diketone-modified derivatives
The molecular modification of diketone-modified
derivatives predominantly changes the carbon-oxygen double bond
(carbonyl group) of curcumin into a carbon-nitrogen double bond.
Due to the properties of three lone pairs of electrons in the
nitrogen atom, these derivatives can be coupled with active
molecules to form curcumin-active molecule conjugates (Fig. 10). In addition, diketone-modified
conjugates may be further combined with aliphatic chain C4-modified
derivatives to form more complex structures (16). Diketone-modified derivative
modification is a relatively novel research direction, which not
only improves the physicochemical properties of curcumin, but also
displays certain physiological activities, such as reducing
β-amyloid secretion in human neuroblastoma SH-SY5Y cells and in CHO
cells, and inhibiting iNOS expression and NO production induced by
lipopolysaccharide in brain microglia (16,51).
Curcumin-piperlongumine (CP)
hybrid
The instability of the chemical structure of
curcumin and the toxic side effects of piperlongumine both limit
their potential applications. Piperlongumine is an alkaloid extract
from Piper longum L., which has been proven to exert
anti-inflammatory and antitumor activities with relatively high
toxicity (52). To overcome these
disadvantages, a novel CP hybrid molecule was designed and
synthesized using a molecular hybridization strategy (Fig. 11). Compared with its parent
compounds, CP displays enhanced structural stability and safety,
which effectively inhibits cell proliferation, and induces
apoptosis mediated by cell cycle arrest and through the regulation
of JNK signaling in lung cancer cells (52).
Metal-chelating curcumin
derivatives
In addition to the aforementioned curcumin
derivatives and hybrids, by pairing or chelating with metal atoms
or metal ions, curcumin may be modified into different derivatives.
As such, two zinc (Zn)-containing complexes have been designed and
synthesized where curcumin and bipyridine were used as ligands
chelated with metal Zn. Curcumin or analogs have also been
coordinated with other metals, such as copper, palladium and
aluminum (Fig. 12) (53–56).
Curcumin may also be modified with a moiety containing a metal atom
to form Zn(II)-curcumin-based coordination complexes, thus the
physicochemical properties and functional activities of curcumin
can be improved (57). These types
of metal-chelating curcumin derivatives have been investigated in
in vitro studies, such as in the human neuroblastoma cell
line SH-SY5Y (57).
In conclusion, in order to overcome the limitations
of curcumin, including poor water solubility, unstable chemical
properties, low bioavailability, fast metabolic rate and
photodegradability, numerous measures have been adopted to modify
curcumin, such as using distearoyl
phosphatidylethanolamine-polyethylene glycol and GC@NPs as carriers
(42). Curcumin micelle formation,
liposome encapsulation, β-cyclodextrin curcumin and food gel
delivery systems have also been constructed to address the
aforementioned limitations (58–61).
Molecular mechanism of curcumin and its
derivatives/analogs as antitumor medications
The antitumor activity of curcumin has been widely
researched regarding the pharmacological functions of curcumin. At
present, studies have reported that antitumor activities of
curcumin and its derivatives/analogs have been exerted in numerous
cancer cell lines, including head and neck squamous cell carcinoma,
lung, breast, prostate, colon and brain cancer (Table I) (34,35,37,38,40,42,44,49,52,55).
 | Table I.Applications of curcumin
derivatives/analogs in cancer cells. |
Table I.
Applications of curcumin
derivatives/analogs in cancer cells.
| Type of cucumin
derivative/analog | Cancer type (cell
line) | (Refs.) |
|---|
| Hydrogenated
curcumin derivatives | Colorectal
adenocarcinoma (Caco-2/human) | (34,35) |
| Halogenated
curcumin derivative | Melanoma
(518A2/human) | (37) |
| Aryl-modified
curcumin derivatives | Hepatocellular
carcinoma (HepG2/human), gastric adenocarcinoma (SGC-7901/human),
lung adenocarcinoma (A549/human), colon cancer (HCT116/human) | (38,40) |
|
Monocarbonyl-modified analogs | Colon cancer
(CT26/mouse) | (44,45) |
| Bis-imino and
bis-amino curcumin derivatives | Breast carcinoma
(MCF7/human) | (49) |
| Diketone-modified
derivatives | Pheochromocytoma
(PC12/mouse) | (51) |
|
Curcumin-piperlongumine hybrid | Lung cancer
(H466/human, H129/human) | (52) |
| Metal-chelating
curcumin derivatives | Human prostate and
colon cancer cells | (55) |
The molecular mechanisms underlying the antitumor
activities of curcumin and its derivatives/analogs include
induction of apoptosis and autophagy, inhibition of cell and
invasion and improving the sensitivity of cancer cells to
anticancer drugs through a variety of signaling pathways. These
mechanisms are involved in inducing or inhibiting the expression of
various types of enzymes, transcription factors, cytokines or
growth factors, such as MAPK (62–64),
cyclooxygenase (COX)-2 (65),
NF-κB (65,66), Wnt/β-catenin (67), STAT (63,68–73),
TNF-α (74) and epidermal growth
factor (EGF) (75). The present
review focused on lung, prostate, breast and colorectal cancer
(CRC) to illustrate the antitumor molecular mechanism of curcumin
and its derivatives/analogs.
Lung cancer
Lung cancer is the leading cause of cancer-related
mortality and has a high incidence rate. The latest cancer report
from the International Agency for Research on Cancer, a subsidiary
of the World Health Organization, revealed that in 2022, there were
2.481 million new cases of lung cancer worldwide, accounting for
12.4% of all new cancer cases globally; therefore, lung cancer is
considered the leading cancer worldwide. In addition, lung cancer
is also the leading cause of cancer-associated mortality; in 2022,
lung cancer caused 1.817 million deaths, accounting for 18.7% of
all cancer deaths (76). Curcumin
is a key polyphenolic nutraceutical compound that is often utilized
in Chinese herbs for the treatment of lung cancer (77). Numerous studies have reported that
curcumin and its derivatives can induce apoptosis in lung cancer by
affecting various molecular pathways, such as NF-κB (63,78,79),
PI3K/Akt/mTOR (80–82), vascular endothelial growth factor,
microRNAs (miRNAs/miRs) and long non-coding RNAs (83–85).
Curcumin can also induce autophagy and cell cycle arrest to
attenuate the viability and proliferation of lung cancer cells
(86). In addition, it has been
found that curcumin can increase the efficacy of radiotherapy and
chemotherapy, and enhance chemotherapy-or radiotherapy-mediated
apoptosis by targeting signaling pathways, such as the EGF receptor
(EGFR) and NF-κB cascades (85).
In tumor cells, curcumin can induce the expression of TNF and other
related factors, thereby inhibiting the activation of NF-κB and
preventing the NF-κB dimer from entering the nucleus to promote
apoptosis (66).
It has been shown that curcumin may exert epigenetic
regulatory effects on miRNAs (83–85,87).
In A427 and A549 lung cancer cells, curcumin administration has
been shown to inhibit cell proliferation, migration, invasion and
viability. Furthermore, curcumin could simultaneously increase the
expression levels of miR-192-5p, and reduce β-catenin, cyclin D1
and c-Myc expression levels. By contrast, genetic knockdown of
miR-192-5p prevents the inhibitory effects of curcumin on the
progression of A427 and A549 cells. A dual-luciferase reporter gene
assay demonstrated that miR-192-5p binds to c-Myc. These results
indicated that upregulation of miR-192-5p, potentially by targeting
c-Myc, may enhance the inhibitory effects of curcumin on non-small
cell lung cancer cells via the Wnt/β-catenin signaling pathway
(87).
Prostate cancer
Prostate cancer is one of the most common and
prevalent types of cancer in men worldwide (76). Previous studies have demonstrated
that curcumin has the ability to inhibit proliferation and induce
apoptosis in prostate cancer cells by interfering with signaling
pathways, such as NF-κB, MAPK and EGFR (88–90).
JARID1D, as a histone H3 lysine 4 demethylase, exhibits low
expression level in advanced prostate cancer, which is involved in
rapid invasion and metastasis in patients with prostate cancer.
Curcumin could increase the expression levels and demethylation
activity of JARID1D, and further affect the androgen receptor and
epithelial-mesenchymal transition (EMT) signaling cascade to
inhibit prostate cancer metastasis (91).
In humans, the ubiquitin-conjugating enzyme E2 C
(UBE2C) is upregulated in prostate cancer compared with benign
prostatic hyperplasia. Administration of curcumin in in
vitro prostate cancer (PCa) cell models decreased the
expression levels of UBE2C and simultaneously increased miR-483-3p
expression levels; notably, a dual-luciferase reporter gene assay
was used to demonstrate the binding of miR-483-3p to UBE2C.
Furthermore, when UBE2C was knocked down by small interfering RNA
(siRNA), PCa cell proliferation, migration and invasion were
inhibited, thus suggesting that curcumin exerts its antitumor
activity via modulation of the UBE2C/miR-483-3p axis, through
reducing UBE2C and increasing miR-483-3p in PCa (92).
The PI3K/Akt/mTOR signaling pathway promotes
apoptosis and inhibits proliferation, and serves a key role in cell
cycle regulation (93). Curcumin
was shown to activate the PI3K/Akt/mTOR signaling pathway in tumor
cells, thereby downregulating the expression of PI3K, Akt and mTOR,
and promoting apoptosis of different types of tumor cells, such as
ovarian carcinoma cells and colon cancer cells (94–96).
In addition to curcumin, certain derivatives have also shown
anticancer activity against prostate cancer. The novel curcumin
analogue NL13 targeting Polo-like kinase 4 (PLK4) presents
effective antitumor properties by disrupting the
PLK4-Akt-CCNB1/CDK1 pathway and induces apoptosis in prostate
cancer (97).
Recently, through in-depth network pharmacology and
molecular docking studies, it has been identified that SRC, PIK3R1,
STAT3, AKT1, HSP90AA1, ESR1, EGFR, HSP90AB1, MAPK8 and MAPK1 are
the core targets of curcumin. Molecular docking experiments have
shown that the binding energy of curcumin to these core targets is
<-1.85 kJ mol−1, which indicates that curcumin can
spontaneously bind to these core targets. Consequently, curcumin
interferes with the cyclic process of prostate cancer cells,
thereby inhibiting their proliferation. These results have been
verified at multiple levels, such as mRNA expression, protein
expression and immune infiltration (98). This finding may provide more
potential targets for curcumin and its derivatives in cancer
treatment.
Breast cancer
Breast cancer is a leading cause of mortality in
women worldwide, which has attracted extensive research attention
due to its high drug resistance and malignancy (76,99).
As a natural medicine, curcumin has been investigated in
combination with various antitumor drugs in breast cancer cells.
When combined with thymoquinone or doxorubicin, curcumin can induce
the apoptosis of MCF-7 and MDA-MB-231 breast cancer cells through
downregulating PI3K and Akt protein levels (100,101). It has been shown that
upregulation of COX-2 is involved in carcinogenesis, invasiveness
and malignant tumor metastasis. Notably, curcumin combined with
celecoxib has been reported to exert a synergistic growth
inhibitory effect through downregulation of COX-2 pathways in
MDA-MB-231 cells (102). When
combined with luteolin, curcumin synergistically inhibits
triple-negative breast cancer by suppressing cell proliferation,
colony formation and transformation via regulation of the IFN and
TGF-β signaling pathways (103).
Due to drug resistance in breast cancer, curcumin
has recently been combined with linc-RoR siRNA. Linc-RoR is a long
intergenic noncoding RNA that modulates stem cell differentiation,
and promotes metastasis and invasion in breast cancer. Using
polyamidoamine dendrimers, synergistic anticancer effects of
co-delivery of linc-RoR siRNA and curcumin have been shown against
MCF-7 breast cancer cells (104).
In MCF-7 cells, curcumin alone has been shown to
decrease cell proliferation via the downregulation of proliferating
cell nuclear antigen, estrogen receptor α, β-catenin, vimentin and
E-cadherin, which are associated with epithelial-mesenchymal
transition (105). Meanwhile the
antitumor activities of various curcumin analogs or derivatives,
such as NC2603, N17, pentagamavunone-1 and dimethyl curcumin
(ASC-J9), have been investigated to induce cell death in breast
cancer cells (106–111).
CRC
CRC ranks third behind lung cancer and prostate
cancer as the most common types of malignant cancer (76,86).
Chronic gut inflammation is a risk factor for colorectal
carcinogenesis. Although patients with CRC often receive
chemotherapy or have their tumors removed during treatment, due to
liver metastases, ~50% of patients suffer from relapses (112,113).
miR-34a is a p53-inducible miRNA with
tumor-suppressive capacities. In a large proportion of CRC cases,
miR-34a and miR-34b/c genes are downregulated, not only commonly
during intestinal carcinogenesis, but also causally in CRC
formation. As a natural phytopolyphenol compound, curcumin has been
shown to induce miR-34a and miR-34b/c expression in a
ROS/Nrf2-dependent and p53-independent manner to suppress CRC
metastasis (114).
miR-21 gene expression levels are upregulated in CRC
cells (115). After curcumin
treatment in HCT116 CRC cells, the cell cycle has been shown to be
arrested in the G2/M phase, which may result in tumor
growth inhibition. In addition, administration of curcumin could
downregulate miR-21 by inhibiting activator protein binding to the
miR-21 promoter (116). In
another study, difluorinated curcumin, a novel curcumin analog, has
been indicated to inhibit the proliferation of colon cancer cells,
by downregulating miR-21 in HCT116 and HT-29 chemoresistant
colorectal cancer cells, and also in SW620 metastatic colon cancer
cells by affecting the miR-21-PTEN-Akt pathway (117).
In CRC cells lines tested (HCT116, SW480, LoVo and
HT29), curcumin treatment has been reported to significantly induce
cell apoptosis by arresting cells in the sub-G1 phase,
and the components of the NOD-like receptor protein 3 (NLRP3)
inflammasome have been revealed to be elevated in SW480 and HCT116
cell lines (118). Curcumin and
crocin treatment could cooperatively reduce cell viability and
induce apoptosis in SW-480 cells by modulating the expression of
Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, Janus kinase 2
(JAK2), STAT3 and Akt1 genes. Furthermore, co-administration of
curcumin and crocin had synergistic effects to increase cell cycle
arrest at sub-G1 phase and to induce autophagy in SW-480
cells (119).
An in vivo study of a CRC mouse model,
curcumin was found to improve response to radiation therapy due to
its ability to target NF-κB (120). In combination with EGFR-related
protein, a pan-erb B inhibitor, curcumin showed enhanced inhibitory
activity against colon cancer cells (121). The Notch1 pathway is involved in
cell differentiation, proliferation, apoptosis and adhesion, and
the anti-apoptotic protein Bcl-2 suppresses the activities of
Notch1 and caspase-3. Curcumin has an inhibitory effect on Bcl-2,
which could restore the activity of the Notch1 pathway and
caspase-3 and lead to the apoptosis of tumor cells (122,123).
Other studies have also shown that curcumin can
inhibit the metastasis and invasion of tumor cells, the formation
of new blood vessels and can reduce the supply of nutrients to
tumor cells (124,125). Curcumin and its
derivatives/analogs, alone or combination with other antitumor
drugs, may exert antitumor effects through multiple molecular
mechanisms in different types of cancer cells. The mechanisms and
applications of curcumin and its derivatives/analogs in other types
of cancer are summarized in Table
II (114,126–139).
| Table II.Summary of curcumin or curcumin
derivatives/analogs in cancer treatment. |
Table II.
Summary of curcumin or curcumin
derivatives/analogs in cancer treatment.
| Agent | Type of cancer | Mechanism | Significance | Clinical
application | (Refs.) |
|---|
| Curcumin | Colorectal
cancer | Regulates
regulatory T cells/T helper 17 cells immune balance. Inhibits
inflammatory pathways, such as NLRP3. Induces
G0/G1 phase arrest. Up-regulation of
proapoptotic protein Bax. | Synergistically
inhibits HCT-116 cell proliferation by combination with 5-FU.
Reduces the need for chemotherapy dose. | Prevention of
inflammation-related cancer. Reduction of drug resistance with
adjuvant chemotherapy. | (126,127) |
|
| Multiple types of
cancer | Regulates ROS
levels and inflammatory microenvironment. Inhibits tumor growth by
multiple signaling pathways, such as the Wnt/β-catenin and Janus
kinase pathways. | Broad-spectrum
antitumor activity in vitro. Enhances the efficacy by
combination with paclitaxel and other drugs. | Multi-target
therapeutic potential. Optimization of bioavailability to improve
efficacy. | (114,128–129) |
| Curcumin/curcumin
derivatives/analog | Oral cancer | Activating the
caspase pathway. Inhibit EGFR/MAPK signaling pathway. Decrease the
expression of MMP-2/9. Inhibit epithelial-mesenchymal
transition. | Inhibits SCC-25
cell proliferation. Reduces tumor volume and increase apoptosis
rate in preclinical models. | Reduces
complications of chemoradiotherapy. Potential adjunctive
therapeutic drugs. | (130–132) |
|
| Hepatocellular
carcinoma | Inhibits NF-κB,
PI3K/Akt and MAPK signaling pathway. Induces cell apoptosis.
Inhibits tumor angiogenesis. | Significantly
inhibits the proliferation of hepatocellular carcinoma cells in
vitro. Prolong survival by combination with sorafenib. | Potential
combination therapy strategies. Improves chemotherapy sensitivity
and reduce side effects. | (133–136) |
| Nanocurcumin | Multiple
myeloma | Improves the water
solubility and target therapy by nanoparticles. Enhances drug
enrichment in tumor tissue. | Nano-delivery
system significantly improves the blood concentration and stability
of curcumin. | Improves the
feasibility of clinical. transformation | (137–139) |
Limitations and side effects of curcumin and
its derivatives/analogs in preclinical and clinical studies
Curcumin, as a natural polyphenolic compound, has
shown potential in the fields of anti-inflammatory, antioxidant and
antitumor activities, and displays various advantages, such as
alleviating chemotherapy side effects, preventing second primary
tumors, improving quality of life for patients with cancer and as
synergistic chemotherapy (140–148) (Table III). However, the unsafety and
side effects of curcumin have attracted much attention in
preclinical and clinical studies (144,149–154). It has been demonstrated that
curcumin and its derivatives present translational potential in
several pharmaceutical fields; however, the existing limitations
(Table III) need to be overcome
through technological innovation and further clinical trials.
Future research should focus on optimizing delivery systems,
scaling up clinical trials and exploring combination treatment
strategies.
| Table III.Advantages and disadvantages of
curcumin and its derivatives/analogs in cancer treatment. |
Table III.
Advantages and disadvantages of
curcumin and its derivatives/analogs in cancer treatment.
| A, Advantages |
|---|
|
|---|
| Advantage |
Characteristics | Intervention | (Refs.) |
|---|
| Alleviating
chemotherapy | Reduces kidney
damage caused by cisplatin. | Dose, 80 mg
nanocurcumin twice daily for 5 days. | (140) |
| side effects | Relieve mouth sores
and pain caused by radiation therapy with | For oral mucositis,
0.1% curcumin mouthwash or 40 mg | (141) |
|
| the topical use of
curcumin mouthwash or nanocurcumin capsules. | nanomicelles (1 min
thrice daily for 3 weeks). |
|
|
| Reduces neuropathy
induced by vincristine. | For peripheral
neuropathy induced by vincristine, 3 mg/kg oral curcumin capsules
twice daily for 3 months. | (142) |
| Prevention of
second primary tumors | Reduces the head
and neck cancer by combination with metformin. | Curcumin (600 mg
tablets) or metformin (500 mg tablets) twice daily for 36
months. | (143) |
| Improvement of the
life quality | Reduces nausea,
decrease appetite, fatigue and other symptoms during radiotherapy
or chemotherapy. | Dose, 500 mg oral
curcumin gel 3 times daily for 7 weeks. | (144) |
|
| Improves radiation
dermatitis (reduced severity score). | Curcumin
administered orally, 800 mg twice daily for 8 weeks. | (145) |
| Synergistic
chemotherapy | Shows synergistic
antitumor effects in colon cancer models combined with paclitaxel,
capecitabine and other chemotherapy drugs. | Co-delivery system
with different curcumin and other chemotherapy drugs. | (146–148) |
|
| B,
Disadvantages |
|
|
Advantage |
Characteristics |
Intervention | (Refs.) |
|
| Low
bioavailability | Oral absorption
rates are low (<1%) and rely on nanomaterials or prodrug
technologies (such as TBP1901) improved targeting. | Dose range,
80–12,000 mg/day, but the efficacy is limited. | (149) |
| Research
limitations | Small sample sizes.
For example, there were only 35–40 cases | Four 500 mg
curcumin capsules, 3 times a day, for 3 weeks, | (150,144) |
|
| in the radiation
dermatitis test of nanocurcumin. | Curcumin (n=20),
Placebo (n=20); 2 g curcumin orally three |
|
|
| High heterogeneity
(I2=95.7% in meta-analysis of radiation
dermatitis). | times per day, for
7 weeks, Curcumin (n=18), Placebo (n=17). |
|
|
| Lack of long-term
follow-up data, such as precancerous lesion studies. |
|
|
| Dose
standardization | Doses vary widely
from study to study; unclear optimal thera | Dose range,
120–1500 mg/day. | (151) |
|
| peutic window. |
|
|
| Potential side
effects | Gastrointestinal
discomfort: diarrhea and nausea (~5%). | Upper limit of safe
dose is typically ≤8 g/day. | (152–154) |
|
| Drug interactions:
may enhance the effect of anticoagulant or hypoglycemic drugs. |
|
|
|
| Risk of
hepatotoxicity: case reports of high doses. |
|
|
Lower bioavailability and
stability
Due to its poor water solubility, rapid metabolism
(half-life, ~1 h) and lower bioavailability (<1%), curcumin
requires a high dose to reach an effective blood concentration,
which also increases the risk of side effects (155). To improve the bioavailability of
curcumin, polymer micelles and liposomes or lipid carriers are
often used (7,15), but these preparations may introduce
new irritant or allergy risks. In addition, due to the unstable
structure of β-diketone, natural curcumin is inclined to degrade
rapidly in the body, requiring a high dose or frequent use,
resulting in cumulative toxicity risk (156). Therefore, optimization of
synthetic derivatives/analogs of curcumin to enhance solubility or
bioavailability is necessary. For example, by removing the
β-diketone structure of curcumin, MACs have shown improved chemical
stability and antitumor activity (44,45).
Preclinical studies have also testified that the hepatotoxicity of
these derivatives is markedly lower compared with that of natural
curcumin, and the anti-inflammatory effect is improved. Chelating
curcumin with metal ions can enhance antioxidant activity and
reduce direct irritation to the gastrointestinal tract (53–56).
Therefore, optimization of synthetic derivatives/analogs of
curcumin or coordinating them with metals, such as zinc, copper,
palladium and aluminum, is ongoing (53–56).
Nanoparticle or liposome encapsulation have been explored to reduce
gastrointestinal irritation by improving solubility and targeting,
reducing the effective dose (113–115).
Research limitations
Curcumin derivatives/analogs have the potential to
reduce kidney damage and neuropathy caused by chemotherapy drugs,
but further clinical data are needed to validate this, and the
safety of their long-term metabolites is of concern. The sample
size in trials so far has been relatively small; for example, only
37 cases were assessed in a previous radiation dermatitis test of
nanocurcumin. Results have also shown high heterogeneity
(I2=95.7% in a meta-analysis of radiation dermatitis)
and lack long-term follow-up data, such as in precancerous lesion
studies (150,144) (Table III). In addition, a large
proportion of studies are small-scale randomized controlled trials
or animal experiments (150,144). Regarding the therapeutic
effectiveness of curcumin derivatives/analogs in patients with
cancer, the optimal dosages for different conditions necessitate
further investigation in a larger scale to provide a specific
clinical recommendations. While structural optimization and
formulation improvements can notably reduce side effects, their
long-term safety needs to be further validated.
Dose standardization issues
Inconsistencies in the use of curcumin and its
derivatives/analogs have been found in clinical trials for cancer
treatment, mainly due to their pharmacokinetic characteristics,
bioavailability and individual differences(149,157). Curcumin has a very low oral
bioavailability (<1%), mainly due to its poor water solubility
and rapid intestinal metabolism. Although plasma concentrations of
curcumin can be increased by modification through liposomes,
nanocarriers or prodrugs, such as TBP1901, difficulties to maintain
effective therapeutic concentrations in clinical trials are present
(149). For example, in a
previous study, the plasma concentration of liposome curcumin at
the maximum tolerated dose in patients was demonstrated to be 3.9
µM, which is notably lower than the effective concentration in
vitro, which is typically 10–50 µM (157). This mismatch between dose and
efficacy results in limited clinical effectiveness.
The metabolic pathway of curcumin and its
derivatives is complex; the half-life is short (1–2 h) and the
pharmacokinetics of different dosage forms are significantly
different. For example, the prodrug TBP1901 is 50-fold more
efficient in bone marrow than in blood, but the mechanism of its
transformation in the human body, which is dependent on
β-glucuronidase (GUSB), is not yet fully understood (149). The results lack a reliable
pharmacokinetic model support for dose design, which makes it
difficult to predict the effective dose range. In vitro
studies have shown that the inhibitory effect of curcumin
derivatives is dose-dependent, but increased doses can trigger
toxic reactions, such as the induction of oxidative stress or
inhibition of key enzyme activities, leading to safety concerns.
Clinical trials often fail to determine the optimal therapeutic
window due to the difficulty of dose increasing (151–154).
The metabolism and efficacy of curcumin are also
influenced by the patient genotype, intestinal flora and tumor
microenvironment. For example, the expression of GUSB in different
tumor tissues is different, which results in poor prodrug
conversion efficiency (149).
Both curcumin β-D-glucuronide and its active metabolite, aglycone
curcumin, were previously detected in the blood after TBP1901
injection in GUSB-proficient mice, whereas only curcumin
β-D-glucuronide was detected in GUSB-impaired mice. These results
suggest that GUSB may serve a pivotal role in the conversion of
TBP1901 into aglycone curcumin in vivo. It has been verified
that TBP1901 itself has minimal antitumor effects in vitro,
whereas it demonstrates notable antitumor effects in vivo.
In addition, inadequate stratification of patient populations in
clinical trials, such as different cancer types or molecular
typing, leads to difficulty in harmonizing dose standards, for
example the wide dose range (120 mg-1,500 mg/day) that has been
suggested has led to conflicting results in a number of studies
(151–154).
A large proportion of existing clinical studies
have focused on short-term efficacy and the evaluation of long-term
safety is insufficient (150,144). For example, curcumin has been
shown to present a risk of hepatotoxicity in animal models, but the
long-term dose threshold in humans has not been defined (151). In addition, curcumin may alter
the metabolism of other drugs through drug interactions during
combination chemotherapy (158),
which means that curcumin-drug interactions should be considered
when curcumin or curcumin analogs are administered in clinical or
preclinical trials. Therefore, dose adjustment is required, but
relevant studies are limited.
Gastrointestinal discomfort and liver
toxicity
The most common side effects of curcumin are
gastrointestinal reactions, including nausea, diarrhea, a burning
feeling in the stomach and bloating (Table III). The irritation may result
from direct stimulation of the gastrointestinal mucosa, especially
at high doses (>8 g/day) or on an empty stomach. Clinical trials
have shown that ~5% of the subjects report mild gastrointestinal
discomfort, but symptoms usually resolve after tapering or stopping
the drug.
Animal studies in preclinical trials have shown
that long-term high-dose intake of curcumin (400 mg/kg/day) may
lead to elevated liver enzymes (ALT and AST) and liver
histopathological changes (152–154,159), possibly related to the
accumulation of metabolites of curcumin in the liver. Previous
clinical studies have not observed significant liver toxicity, but
case reports suggest that excessive doses (>12 g/day) or
prolonged use may cause liver dysfunction, especially in patients
with underlying liver disease. For example, one study has reported
a case of autoimmune hepatitis induced by curcumin supplements
(152,154,160). Although up to now, there are few
reports on liver toxicity caused by curcumin or curcumin analogs,
the existing reports imply the potential importance of curcumin as
drug supplementation triggering liver injury.
In addition, patients with liver and gallbladder
diseases, bleeding disorders and those taking anticoagulant or
hypoglycemic drugs should be cautious of using curcumin as
treatment (154). Curcumin
inhibits platelet aggregation and may increase the risk of bleeding
(161). In addition, curcumin can
enhance the hypoglycemic effect, leading to a risk of hypoglycemia.
Anticoagulants (such as warfarin) and hypoglycemic drugs should
therefore not be taken with curcumin supplements (162,163).
In summary, the safety of curcumin is closely
related to its chemical structure, dose and individual differences.
The development of derivatives has improved its choice clinical
application, but it is still necessary to weigh the efficacy and
potential risks.
Other biological effects of curcumin or its
derivatives/analogs
Antioxidant effects
A number of diseases are closely related to
increased levels of ROS in the body, thus removing excess ROS is an
important method for disease prevention and pain relief. Curcumin
or its derivatives, as a class of polyphenols, are able to adsorb
free radicals, thus exerting antioxidant effects in the body
(164). Numerous studies have
also shown that the phenolic hydroxyl group, β-diketo moieties and
carbon-carbon double bond of curcumin are preferred structures for
removing ROS. The antioxidant activity of curcumin is similar to
that of vitamin C and E, which may regulate the physiological
activity of some antioxidant enzymes, such as glutathione (GSH)
peroxidase, catalase and superoxide dismutase. Curcumin may also
increase the content of GSH in cells to clear ROS, which protects
lipids or hemoglobin from oxidation (164–166).
Anti-inflammatory effects
The resistance of curcumin to inflammation is
mainly mediated by the inflammatory pathways of NF-κB (167), JAK/STAT, PI3K/Akt (168), MAPK, Nrf2/antioxidant chemical
response elements and the NLRP3 inflammasome (169,170). In addition, curcumin can reduce
the expression of the inflammatory factors IL-1β, IL-6, TNF-α,
prostaglandin E2 and COX-2 by inhibiting the degradation of IκBα
and the phosphorylation of NF-κB subunits p65 and p50 (167), thus possessing anti-inflammatory
effects.
In the JAK/STAT pathway, curcumin can significantly
reduce the levels of JAK/STAT conjugate, the expression levels of
inflammatory factors and can alleviate the inflammatory response
(168). Similarly, curcumin can
directly reduce the levels of inflammatory factors during the
inflammatory process or reduce the levels of inflammatory factor
precursors and pro-inflammatory factors to achieve
anti-inflammatory effects (171–173). In summary, curcumin can exert
anti-inflammatory action through multiple signaling pathways at
cellular level.
Antibacterial effects
Since the 1960s, methicillin-resistant
Staphylococcus aureus (MRSA) has disseminated globally and
has become a leading cause of bacterial infections in both
healthcare and community settings. Experimental results have shown
that curcumin has notable inhibitory effects on S. aureus,
Escherichia coli, Bacillus subtilis and Clostridium
aerogenes (174–176). For MRSA, curcumin has shown a
significant inhibitory effect at a concentration of 125–500 µg/ml
and acts synergistically with oxacillin. Curcumin is therefore a
potential candidate for the development of drug formulations to
treat MRSA infections (177,178).
The antibacterial effects of curcumin are reflected
in two aspects: i) The chemical structure of curcumin itself serves
an antibacterial role; and ii) curcumin is a natural
photosensitizer, which can enhance antibacterial activity and
produce cytotoxic ROS under the irradiation of blue light. ROS can
facilitate oxidative stress reaction in bacterial infections and
lead to bacterial adhesion, cell disruption and DNA damage.
Therefore, curcumin alone or in combination with other
antibacterial drugs may be widely utilized in the pharmaceutical
field (179).
Antiviral effects
The antiviral capability of curcumin or its
derivatives is demonstrated in two aspects: i) Curcumin and its
derivatives directly act on viruses; and ii) curcumin and its
derivatives indirectly resist viruses by regulating the relevant
host proteins.
Direct antiviral effect
In vitro studies have shown that curcumin
can directly interfere with the adsorption of the viral envelope to
host cells without degrading viral nucleic acid or destroying viral
particles. The molecular mechanism is that the structure of
unsaturated diketone moieties of curcumin can influence the
fluidity of the viral envelope, leading to the conformation
alteration of glycoproteins and reduce the adsorption of host cell
membranes (180–182).
In addition to weakening the adsorption of viruses
on host cells, curcumin can target some virus-related enzymes or
proteins and interfere with viral replication. For example,
curcumin has shown good inhibitory effect against hepatitis C and B
viruses (182,183). Curcumin can suppress the function
of viral integrase by binding to acidic amino acid residues in the
catalytic core region. At the same time, curcumin can induce the
degradation of key proteins, such as the transactivator Tat, and
inhibit the proliferation of HIV (184,185).
Indirect antiviral effect
By regulating various host-related signal pathways,
curcumin may induce antiviral effects. For example, curcumin can
activate the Nrf2/HO-1 signaling pathway of host cells, stimulate
the production of a variety of antioxidant enzymes and
simultaneously inhibit multiple inflammatory pathways stimulated by
viruses and release IFN to achieve antiviral effects (184,186,187).
Neuroprotective effect
Alzheimer's disease (AD) is a progressive, complex
neurodegenerative disorder that poses an increasing threat to
healthcare systems around the world due to the rapid increase in
the aging population. This aging disorder is associated with
amyloid-β peptide aggregation, tau hyperphosphorylation,
neuroinflammation and oxidative stress. Thus far, therapeutic
strategies designed to treat AD neurodegeneration have proven
unsuccessful, the reason for this may be that single-target drugs
are unable to limit the progressive deterioration of brain
functions (188–191). Therefore, the therapeutic
strategies used to treat AD have switched from over-emphasizing a
single deleterious process to considering AD neurodegeneration as
the result of different pathogenic mechanisms and their interplay.
Phytochemical compounds are emerging as a natural source and as
multi-target agents in traditional pharmacological medicine.
Curcumin has been considered such a natural multi-target agent
(188).
Previous studies have shown that curcumin can
improve the memory ability and development of the hippocampal nerve
in AD model rats (189–191). Curcumin has the capability to
prevent cerebral stroke edema, and to reduce cerebral
ischemia-reperfusion injury, cerebral ischemia injury and spinal
cord injury (192–194). In addition, curcumin may serve a
role in the cerebral cortex, inhibit the activation of hippocampal
microglia and the release of inflammatory factors and exert
anti-depressive effects (195).
Curcumin, a natural product, has the ability to induce hHO-1 and
phase II enzyme expression in astrocytes and cultured hippocampal
neurons, potentially via activation of the transcription factor
Nrf2, which exerts a significant cytoprotective effect on cultured
neurons exposed to oxidative stress (196,197). These results indicate that
curcumin may have the therapeutic capacity to restore cellular
homeostasis and rebalance redox equilibrium (196), thus counteracting
neurodegenerative inflammation in AD and multiple sclerosis,
producing positive cognitive and behavioral outcomes (194,198). The development of novel delivery
systems and formulations may enhance the therapeutic potential of
curcumin in the treatment of neurodegenerative diseases.
Conclusions
Curcumin, a polyphenolic natural constituent
derived from Curcuma longa and other plants, has been shown
to exert potential antitumor activities in various types of cancer,
and may present antioxidant, anti-inflammatory, anti-depressive and
neuroprotective biological roles. The molecular mechanisms of its
antitumor activities involve a variety of enzymes, transcription
factors, cytokines and growth factors, such as MAPK, COX-2,
PI3K/Akt, NF-κB, Wnt/β-catenin, STAT, TNF-α and EGF. Therefore,
curcumin gained increasing attention from researchers and may be
considered a promising novel compound with low toxicity to a
variety of biological targets.
Since ancient times, curcumin, with turmeric as the
main carrier, has been used in traditional Chinese herbs, and has
been recorded in the ‘Compendium of Materia Medica’, ‘Shennong
Materia Medica’, ‘Qianjin Fang’ and ‘Tang Materia Medica’. Turmeric
has been a staple in traditional dishes and medicines since ancient
times, especially in Southeast Asia, India and China.
The unique molecular structure of curcumin has
endowed it with potential and value in food and pharmaceutical
research, especially in cancer treatment. Despite this, challenges
remain regarding its limited bioavailability and the scarcity of
comprehensive human clinical trials. In order to overcome the
limitations of curcumin, curcumin derivatives or analogs have been
developed and applications in clinical research and medical drugs
investigated. At present, the key concept regarding the design and
synthesis of curcumin derivatives is that some structural fragments
of curcumin can be modified to retain or moderately enhance the
basic biological activities of curcumin, which may thus improve the
stability, solubility and bioavailability of curcumin and reducing
toxicity. In addition to modifications of the curcumin molecule,
suitable drug carrier materials have been developed for its
delivery. With the ongoing development of research, additional
pharmacological functions of curcumin may be identified, including
the promotion of wound healing, the reduction of blood glucose
levels and potential applications in the treatment of diabetes and
AIDS, which reflect the potential of curcumin in the field of novel
therapeutic strategies or as a treatment adjunct, and further
underscore the potential of traditional medicine in the modern
medical system.
Acknowledgements
No applicable.
Funding
This work was supported by grants from the Natural Science
Foundation of Shandong Province (grant no. ZR2020MC066).
Availability of data and materials
Not applicable.
Authors' contributions
ZL performed data collection and manuscript
drafting. WY performed data collection and plotting. WQ wrote and
revised the manuscript. Data authentication is not applicable. All
authors read and approved the final manuscript.
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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