Curcumin: Epigenetic Modulation and Tumor Immunity in Antitumor Therapy

Abstract

Curcumin (turmeric) is the main ingredient of the Chinese herbal turmeric rhizome, used to treat tumors, diabetes, inflammation, neurodegenerative diseases, cardiovascular diseases, metabolic syndrome, and liver diseases. The antitumor effects of curcumin have received even more attention. One of the main mechanisms of the antitumor effects includes inhibition of tumor invasion and migration, induction of tumor cell apoptosis, and inhibition of various cell signaling pathways. It has been found that the antitumor biological activity of curcumin in the body is associated with epigenetic mechanisms. That also implies that curcumin may act as a potential epigenetic modulator to influence the development of tumor diseases. The immune system plays an essential role in the development of tumorigenesis. Tumor immunotherapy is currently one of the most promising research directions in the field of tumor therapy. Curcumin has been found to have significant regulatory effects on tumor immunity and is expected to be a novel adjuvant for tumor immunity. This paper summarizes the antitumor effects of curcumin from four aspects: molecular and epigenetic mechanisms of curcumin against a tumor, mechanisms of curcumin modulation of tumor immunotherapy, reversal of chemotherapy resistance, and a novel drug delivery system of curcumin, which provide new directions for the development of new antitumor drugs.

Keywords

Curcuma longa. - Zingiberaceae - turmeric - curcumin - antitumor molecular mechanism - epigenetics - tumor immunity - drug delivery system

Abbreviations

bFGF: basic fibroblast growth tactor

COX-2: cyclooxygenase-2

CSCs: cancer stem cells

CUR-PEG: combination of curcumin-polyethylene glycol conjugate

DNAMT3A: DNA methyltransferase 3A

ERK: extracellular-signal-regulated kinases

GRB2: growth factor receptor binding protein 2

HMGB1: high mobility group protein B1

ICAM-1: intercellular adhesion molecule-

ICs: immune checkpoints

IL-6: interleukin-6

IL-8: interleukin-8

JAK/STAT: Janus Kinase/Signal transducers and activators of transcription

Ln-cRNA: long non-coding RNAs

LNRs: Lin12/Notch repeats

MARCKS: myristoylated alanine-rich protein kinase C substrate

MDR: multidrug resistance

miRNAs: MicroRNAs

MMP: matrix metalloproteinases

MMP-9: matrix metalloproteinase-9

mTOR: mammalian target of rapamycin

PD-1: programmed cell death protein 1

PDR: prodrug resistance

PI3K: phosphatidylinositide-3-kinases

PKC: protein kinase C

PPNMs: prepared a new type of nano micelles

PRMT5: protein concentrations of arginine methyltransferase 5

RT-PCR: reverse transcription polymerase chain reaction

TGF-β1: transforming growth factor-β1

TLR2: Toll-like receptor 2

TLR4: Toll-like receptor 4

TNF-α : tumor necrosis factor-α

VCR: vincristine-resistant

VEGF-D: vascular endothelial growth factor D

VEGFV: vascular endothelial growth factor
 

Introduction

Cancer is a severe threat to human health, and its prevention and treatment have become a global problem [1]. As a worldwide public health problem, the number of people dying from cancer has reached 900 000 yearly [1], [2]. Radiotherapy and chemotherapy are common treatments for cancer, but while killing cancer cells, they also damage the bodyʼs normal cells [3]. Despite the significant progress in oncology treatment, the morbidity and mortality of malignant tumors remain high [1], [2]. Therefore, searching for more efficient and less toxic therapeutic strategies for tumor treatment remains the focus of current research.

Curcumin is a flavin pigment extracted from the rhizome of Curcuma longa L. (Zingiberaceae), which is a lipid-soluble polyphenol with unsaturated aliphatic and aromatic groups in the main chain, molecular formula C₂₁H₂₀O₆, chemical name 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-one ([Fig. 1]). Curcumin is a hydrophobic polyphenol soluble in ethanol, acetone, and dimethyl sulfoxide. It has various biological and pharmacological activities for treating tumors, diabetes, inflammation, neurodegenerative diseases, cardiovascular diseases, metabolic syndrome, and liver diseases [4]. In recent years, the application of curcumin in antitumor treatment has received extensive attention from researchers. Its actions and mechanisms mainly include inhibition of tumor invasion and migration, induction of tumor cell apoptosis, and inhibition of various cell signaling pathways. Other studies have shown that the biological activity of curcumin in the organism may be regulated by different epigenetic mechanisms, which also suggests that curcumin may act as a potential epigenetic modulator to influence tumor development [5].

Fig. 1 The molecular structure of curcumin.

Tumor immunotherapy is one of the most promising research directions in tumor treatment. Its therapeutic tools mainly include successive cell therapy, immunomodulatory therapy, tumor vaccine therapy, and targeted molecular therapy. In recent years, curcumin has been increasingly used in tumor immunotherapy. The anti-tumor effect is achieved by modulating the expression and activity of the bodyʼs intrinsic immune system, acquired immune system, and tumor-associated molecules in combination with immune checkpoint inhibitors and other tumor immunotherapy approach [6], [7], [8].

In this paper, we review the molecular mechanism of the antitumor effect of curcumin, the mechanism of immunomodulatory effect of curcumin, the reversal of tumor chemotherapy resistance, and the progress of research into a novel drug delivery system of curcumin based on the literature data of curcumin in tumor cells, animal models, and clinical trials, in order to provide new directions for the research of new antitumor drugs and clinical treatment of tumor with curcumin ([Fig. 1]).

Molecular Mechanism of Curcumin Against Tumors

Promotion of tumor cell apoptosis

Apoptosis is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. These three phenomena are prevalent in the biological world [9]. Curcumin promotes tumor cell apoptosis and can inhibit gastric cancer cell proliferation and induce apoptosis by activating the p53 signaling pathway through the upregulation of p53 and p21 [10], [11]. In addition, it also enhances the cell cycle blocking effect of paclitaxel on glioma cell C6, increases its cell proliferation inhibitory activity, increases the expression of pro-apoptotic proteins p53 and p21, activates caspase-3, and decreases the anti-apoptotic molecule Bcl-2, leading to apoptosis [12]. Curcumin inhibits the proliferation and promotes apoptosis of prostate cancer cells in vitro by inhibiting the activation of the intracellular segment (NICD) through down-regulation of the expression of Notch1 and Jagged-1 genes in the Notch receptor family, which in turn affects the expression of its downstream target gene, Bcl-2, and promotes apoptosis [13]. By inhibiting the Wnt/β-catenin signaling pathway, it attenuates tumor cell viability, induces apoptosis, and significantly suppresses the levels of Wnt3a, LRP6, phosphorylated LRP6, β-catenin, phosphorylated β-catenin, C-myc, and survivin [14]. Inhibition of the PI3K signaling pathway by down-regulation of PI3K, phosphorylated protein kinase B (pAkt), and the phosphorylated rapamycin target protein (p-mTOR) inhibits proliferation and induces apoptosis in gastric cancer cell lines [10], [11]. Curcumin activates the p38 MAPK and JNK pathways and promotes apoptosis, as well as induces apoptosis by regulating MAPK/NF-κB, up-regulating the p53/p21 pathway, down-regulating cyclin1 expression, and increasing the expression of Bax/caspase-3, leading to cell arrest in the G1 phase [15], [16]. Curcumin reduces cancer cell metastasis and invasion by inhibiting the activity of the JAK/STAT signaling pathway, inhibiting JAK/STAT3 phosphorylation and the expression of STAT3 downstream targets such as cell cycle protein B1, Bcl-xL, VEGF, and ICAM-1 [17]. Curcumin activates Bax protein expression and inhibits Bcl-2 protein expression to activate the Caspase-3 signaling pathway and promote tumor cell apoptosis [18], [19], [20]. Curcumin reduces the expression of MMP-2 and MMP-9 and the phosphorylation of ERK1/2, thereby inhibiting the metastasis and invasion of cancer cells [21]. Curcumin induces apoptosis by opening the ATP-sensitive potassium pathway, leading to loss of mitochondrial membrane potential (MMP) [22]. Meanwhile, curcumin induces endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells, initiating the Fas signaling apoptotic pathway [23], [24].

Induction of autophagy in tumor cells

Cellular autophagy is the directed transport of cytoplasmic substrates, macromolecules, and excess or damaged organelles to the lysosome for degradation in response to hypoxia, metabolic stress, and ATP depletion [25], [26]. Curcumin is able to regulate cellular autophagy by affecting the AMPK-mTOR signaling pathway. In response to a decrease in intracellular ATP or an increase in the AMP/ATP ratio, AMPK inhibits the activity of mTORC1, which in turn deregulates the inhibitory effect of mTORC1 on cellular autophagy [27], [28], [29]. Curcumin-treated lung adenocarcinoma A549 cells showed autophagosomes and autophagolysosomes, and the inhibition of autophagy increased the survival rate of A549 cells, suggesting that curcumin regulates the autophagic response associated with tumor survival [30]. And it can upregulate the level of Beclin-1 protein (Beclin-1 is a key protein in the autophagy process, interacting with Bcl-2 family proteins to regulate the balance of autophagy and apoptosis) and autophagy-associated light-chain protein 3-II (LC3-II) to promote autophagy in human myeloid leukemia K562 cells [31]. Curcumin may affect the expression of autophagy-related genes by regulating the transcription factor TFEB, but the exact mechanism needs to be further investigated. Curcumin regulates autophagy and apoptosis by activating endoplasmic reticulum stress-regulated mitochondrial Ca2+ signaling; when curcumin acts on hepatocellular carcinoma Huh-7 cells, it activates endoplasmic reticulum stress signaling, leading to mitochondrial Ca2+ uptake, cytochrome c release, and initiation of apoptosis [32]. Curcumin decreased the expression of phosphorylated AKT, mTOR, and S6K1 when inducing autophagy in human melanoma A375 and C8161 cells, as well as in gastric cancer SGC-7901 and BGC-823 cells, suggesting that curcumin inhibits the PI3K and AKT-mTORC1 signaling pathways and promotes cellular autophagy [10], [24]. Curcumin promotes vacuole formation and LC3-I to LC3-II conversion and induces autophagy in oral squamous tumor cells [33].

Inhibition of NF-κB activation

NF-κB controls a large number of tumor-related cell signaling pathways. Curcumin inhibits the expression of NF-κB [34]. NF-κB activates tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, STAT3, cyclooxygenase-2 (COX-2), Bcl-2, matrix metalloproteinases, and vascular endothelial growth factor (VEGF), which in turn stimulate ROS, generate chronic inflammation, and lead to tumor growth [35]. Curcumin prevents the proliferation and invasion of cervical cancer HeLa cells by inhibiting the NF-κB and Wnt/β pathways [36] and also inhibits the proliferation, invasion, and metastasis of breast cancer cells by targeting the NF-κB signaling pathway [37]. Curcumin inhibits cancer cell proliferation and cell cycle protein D expression by down-regulating NF-κB expression, leading to cell cycle arrest in G2/M and G2/S phases [33]. Further studies [38] showed that curcumin inhibited IκB-α (kappa B-α inhibitor) phosphorylation and promoted NF-κB degradation.

Inhibition of tumor angiogenesis and related growth factors

Tumor angiogenesis influences tumor growth and metastasis. Vascular endothelial growth factor (VEGF) promotes angiogenesis and tumor cell proliferation through an autocrine pathway that binds to endothelial cell surface receptors on blood vessels and lymphatic vessels and to tumor cell surface receptors. Signal transducer and activator of transcription 3 (STAT3) is highly expressed in tumors and is closely associated with tumor cell stage, depth of infiltration, lymph node metastasis and tumor grade [39]. Curcumin inhibits gastric cancer proliferation by down-regulating the DEC1-HIF-1a-STAT3-VEGF signaling pathway. Huang et al. [40] reported the important role of tumor mesenchymal stem cells (MSCs) in mediating tumor angiogenesis and found that curcumin inhibited the pro-angiogenic effects of GC-MSCs, possibly by inhibiting the NF-κB/VEGF signaling pathway, eliminating the role of cancer-derived MSCs in driving tubule formation, migration, and colony formation in human umbilical vein endothelial cells (HUVEC). Other studies have shown that curcumin inhibits angiogenesis by down-regulating the expression of VEGF, angiopoietin-1 (Ang-1), Ang-2, PDGF, COX-2, hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF). COX-2, hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF) expression inhibits angiogenesis. It also inhibits angiogenesis through the inhibition of NF-κB, extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), pho-sphatidylinositol 3-kinase (PI3K), and matrix metalloproteinases [41]. Fan et al. [42] found that curcumin has a bi-directional regulatory effect in an animal model of transplanted lung cancer combined with ischemia. Its mechanism of action may be through bidirectional regulation of the HIF-1α/mTOR/VEGF/VEGFR signaling pathway. Further proteomics studies confirmed that it reversed neutrophil elastase (NE)-induced angiogenesis in lung cancer tissues and could directly bind to NE or further inhibit NE by promoting the expression of α1- antitrypsin, suggesting that this compound may have a beneficial impact on the treatment of clinical ischemia combined with tumors.

High mobility group protein B1 (high-mobility group box-1, HMGB1) expression

High-mobility group protein B1 (HMGB1) is associated with vascular endothelial growth factor D (VEGF-D)-induced tumor lymphangiogenesis and tumor metastasis [43]. HMGB1 binds to different cell surface receptors such as Toll-like receptor 2 (TLR2), TLR4, and late glycosylation end product receptors to act on target cells and promote inflammation and tumor progression [44]. The effect of curcumin 50 µmol/L on the SGC-7901 cell line revealed that curcumin might inhibit lymphangiogenesis in gastric cancer by suppressing the HMGB1/VEGF-D signaling pathway [45]. The effect of curcumin on lymphatic vessel density in gastric cancer in vivo was observed by establishing a gastric cancer xenograft tumor model in nude mice, and curcumin was found to inhibit lymph node metastasis in gastric cancer [46]. AFRIN et al. [47] showed that curcumin inhibited the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma in mice by reducing the nuclear translocation of HMGB1 and NF-κB.

Inhibition of microtubule protein polymerization

Microtubules are polymers of α- and β-microtubule protein heterodimers, essential components of the eukaryotic cytoskeleton. Because interference with microtubule dynamics can stop the tumor cell cycle and induce apoptosis, microtubulin has become a preferred target for developing antitumor drugs [48], [49]. Studies with cervical cancer HeLa cells and breast cancer MCF-7 cells show that curcumin inhibits microtubule protein polymerization and promotes interphase and mitotic microtubule depolymerization [50]. Similarly, curcumin inhibits the dynamic instability of microtubules in breast cancer MCF-7 cells [51]. Therefore, curcumin can inhibit microtubule protein polymerization and act as an antitumor agent, which provides a new option for screening natural antitumor drugs and developing new drugs ([Fig. 2]).

Fig. 2 Molecular mechanism of Curcuminʼs antitumor activity. a Mechanism of curcumin-induced apoptosis in tumor cells. b Mechanism of curcumin inhibition of tumor cell proliferation.

Modulation of Tumor Immunity

Modulation of the intrinsic immune system

Intrinsic immune cells are the mainstay of the intrinsic immune response phase and include phagocytes such as macrophages, dendritic cells, and natural killer cells. Activated macrophages include both M1 and M2 phenotypes. M1-type macrophages, or classically activated macrophages, have antitumor effects, whereas M2-type macrophages, or selectively activated macrophages, promote tumor growth, metastasis, and invasion [52]. Curcumin can modulate the intrinsic immune system by promoting the conversion of macrophages to the M1 type, promoting the activation of natural killer cells and recruiting mature dendritic cells to clear tumors ([Fig. 3]). Studies have shown that curcumin treatment inhibits STAT3 and IL-10 expression, induces antitumor immune responses, attenuates inhibition of natural killer cell activity by tumor cells [53], [54], and promotes apoptosis of tumor cells by enhancing recruitment of natural killer cells and cytotoxic T cells through specific combinations (e.g., TriCurin) [55]. In addition, curcumin can activate the immune system [56], upregulate TNF-α and IFN-γ expression, and effectively inhibit tumor growth and metastasis.

Fig. 3 Curcumin regulates the immune system.

Modulation of the acquired immune system

Regulation of the acquired immune system involves specific immune responses in which CD8+ T lymphocytes (cytotoxic T cells) and Th1 cells play a key role in antitumor immunity, whereas regulatory T cells (Treg) may inhibit antitumor immune responses [57]. Curcumin activates the acquired immune system against tumors and promotes the proliferation of central memory T cells and effector memory T cells through the following mechanisms: suppressing Treg cells and reducing their inhibitory effect on immune responses; enhancement of T cell proliferation and restoration of T cell numbers in the tumor host; induces a shift from Th2-type to Th1-type immune responses and attenuates tumor suppression of T cells; inhibits the expression of TGF-β and IL-10 and reduces Treg cell activity; reduces the suppression of tumor immune response by Treg cells by down-regulating CTLA-4 expression and regulating IL-2 levels [58], [59], [60].

Regulation of the expression and activity of tumor immune-related molecules

Tumors can promote T-cell apoptosis by secreting prostaglandin E2, and curcumin can inhibit this effect and prevent T-cell apoptosis induced by tumors ([Fig. 3]) [61]. Curcumin and basil polysaccharides down-regulate the expression of OPN, CD44, and MMP-9, with curcumin inhibiting CD44 more significantly [62] and inhibiting the expression and activity of IDO, reducing the suppression of T cell responses [63]. Meanwhile, curcumin inhibits CSN5 expression, decreases PD-L1 stability, and reduces tumor cell inhibition of specific CD8+ T cells [64].

Curcumin combined with immune checkpoint inhibitors for tumor treatment

Immune checkpoints (ICs) are a class of immunosuppressive molecules that regulate the bodyʼs immune strength. However, when ICs are over-expressed or over-functioning, the bodyʼs immunity is depressed, allowing tumors to grow and develop. Immune checkpoint inhibitors (ICIs) have recently been a hot topic in tumor immunotherapy. ICIs restore the pernicious effect of T cells on tumors by blocking immune checkpoints, thus blocking tumor immune escape [50]. The primary immune checkpoint inhibitors currently on the market are PD-1/PD-L1 inhibitors and IDO inhibitors, while curcumin can be used in combination with immune checkpoint inhibitors for oncology treatment.

CD8+ T cells express PD-1 upon activation, while tumor cells express PD-L1, and the combination of the two inhibits the anti-tumor function of CD8+ T cells. PD-1/PD-L1 antibodies, as one of the effective means of treating tumors, can block this inhibitory effect. Curcumin in combination with PD-1/PD-L1 inhibitors shows new potential in tumor therapy. Curcumin inhibits STAT3 activity, restores dendritic cell activity, enhances induction of tumor antigen-specific T cells, and shows synergistic antitumor activity with the PD-1/PD-L1 antibody in tumor models. A synergistic effect with anti-PD-1 slows down proliferation of hepatocellular carcinoma cells, activates lymphocytes, inhibits immune evasion, down-regulates TGF-β1 expression, and improves the tumor microenvironment [65]. In addition, the combination of curcumin and sildenafil enhances the efficacy of the PD-1 antibody and reduces the growth rate of gastrointestinal tumors. Curcumin also inhibits NF-κB and STAT3 activities, enhances the function of tumor antigen-specific T-cells, and possesses significant synergistic antitumor activity with the PD-L1 antibody [66]. In addition to PD-1/PD-L1, IDO is also an immune checkpoint frequently used as a therapeutic target in tumor immunotherapy, which inhibits the proliferation and differentiation of immune cells, thus allowing tumors to evade the bodyʼs immune surveillance. Dai et al. [67] prepared the charge transfer delivery nanosystem PCPCD@NLG919, which is sensitive to acid-base and redox reactions, and loaded it with IDO inhibitor NLG919 and curcumin, which significantly promoted the proliferation of T cells, tumor-infiltrating B cells, and natural killer cells, as well as the maturation of dendritic cells in both in vitro and in vivo experiments, and efficiently induced apoptosis and inhibited tumor metastasis in vitro.

Curcumin combined with other tumor immunotherapies for tumor treatment

The combination of curcumin and cell-peripheral immunotherapy showed synergistic antitumor effects. Chang et al. [68] found that curcumin could alter the tumor microenvironment, enhance the cytotoxicity of CD8+ T cells against tumors, up-regulate the number of CD8+ T cells, inhibit the expression of TGF-β and IDO in tumor cells, and effectively reduce the number of Treg cells. Tumor vaccines are a type of active immunotherapy, and the combination of curcumin and tumor vaccines shows therapeutic potential. Lu et al. [69] prepared a curcumin-polyethylene glycol conjugate (CUR-PEG) and Trp2 peptide vaccine combination for the treatment of melanoma and found that the combination significantly inhibited the expression of STAT3, IL-6, and CCL2, down-regulated the level of Treg cells, promoted M1 to M2 conversion, and increased CD8+ T cells. In melanoma treatment, the combination of curcumin and FAPα vaccine exhibited synergistic antitumor effects, significantly inhibiting the growth of melanoma and prolonging the survival of mice [70]. Liu et al. [71] combined curcumin and nanovaccines in postoperative tumor therapy, effectively inducing immunogenic apoptosis of residual cancer cells, promoting CD8+ T lymphocyte infiltration within the tumor, significantly enhancing specific T-cell immunity and inhibition of local recurrence and metastasis of the tumor. In addition to PD-1/PD-L1, IDO is also a therapeutic target in tumor immunotherapy. Dai et al. [67] prepared a charge-transfer delivery nanosystem PCPCD@NLG919, which is sensitive to acid-base and redox reactions and loaded with the IDO inhibitors NLG919 and curcumin, which significantly promoted the T cells, tumor-infiltrating B-cells, and natural killer cell proliferation, as well as dendritic cell maturation, and efficiently induced tumor cell apoptosis and inhibited tumor metastasis in vitro.

Reversal of Chemotherapy Resistance

Chemotherapeutic resistance (chemoresistance) refers to the reduced sensitivity of cancer cells to chemotherapeutic drugs, resulting in resistance, and can be classified as congenital or acquired resistance or as prodrug resistance (PDR) and multidrug resistance (MDR) [72]. In a xenograft model, the combination of curcumin and 5-FU significantly inhibited tumor growth more than 5-FU alone, suggesting that curcumin reversed the drug-resistant effect of 5-FU, and the combination treatment increased the expression of miR-200C, confirming that curcumin treatment led to the up-regulation of miR-200C expression, which was associated with the inhibition of EMT (epithelial-mesenchymal transition) [73]. In the irinotecan-resistant colon cancer model, curcumin was able to reverse drug resistance by modulating the EMT pathway, up-regulating E-cadherin expression, and down-regulating waveform protein and N-cadherin expression [74]. Curcumin significantly inhibited the expression of CSC (cancer stem cell) recognition markers, reduced the characteristics of colonic CSCs, and induced apoptosis, reversing resistance to irinotecan [75].

Combination therapy with adriamycin (Dox-Cur) significantly reduces tumor cell survival, tumor ball formation, migration, and invasion, and the anticancer activity of the combination therapy is higher than that of the therapy alone [76]. Combination with chemotherapeutic agents reduces NF-κB activation, decreases Bcl-2 and Bcl-xL expression, enhances chemotherapy-induced apoptosis, and has a chemo-sensitizing effect [77]. Curcumin reversed multidrug resistance in the vincristine-resistant human gastric cancer cell line SGC-7901/VCR, which may be related to reducing the function and expression of P-glycoprotein (P-gp) and promoting the activation of Caspase-3 [78]. Curcumin enhanced the pro-apoptotic effect of cisplatin on SGC-7901 cells, possibly by inhibiting the expression of the p-Akt gene and Bcl-2 protein, while upregulating the expression of T-Akt and p53 genes [77].

Epigenetic Mechanism of Curcumin Antitumor Effect

Altered DNA methylation status

DNA methylation is an epigenetic modification in the mammalian genome that is closely associated with gene expression regulation, transposon repression, aging, and cancer development [79], [80], [81]. It usually occurs in CpG islands, especially in 70% of the CpG dinucleotides in mammals [82]. DNA methylation has been associated with transcriptional silencing, and in particular, the methylation status of promoter CpG islands is negatively correlated with the level of gene expression, i.e., hypermethylation leads to transcriptional silencing, whereas hypomethylation promotes gene transcription. In addition, methylation of gene bodies is not associated with transcriptional repression and may be due to selective activation and selective shearing of promoters within genes. Altered genomic methylation is one of the main features of cancer cells and is usually associated with overexpression of DNA methylation and demethylation enzymes.

Curcumin, as a DNA methylation transferase inhibitor, can regulate the expression of related genes by (i) modulating the activity of related enzymes during the maintenance of DNA methylation and (ii) regulating the expression of DNA methylation enzymes. Curcumin can directly bind to DNA methyltransferase 1 (DNMT1) and covalently block the sulfur-catalyzing effect of DNMT1, thus inhibiting the activity of DNMT1 and significantly reducing the protein expression level of DNMT1 in breast cancer cells [20]. In addition, curcumin promotes p21 expression through mitochondrial oxidative damage, and the upregulation of p21 further inhibits DNMT1 expression through the p53-p21/GADD45A-cyclin/CDK-Rb/E2F-DNMT1 axis, which promotes genomic DNA demethylation and induces apoptosis in gastric cancer cells [83]. Curcumin also enhances p21 expression by decreasing the methylation level of the p21 promoter and may simultaneously promote p21 expression during tumor suppression through multiple mechanisms [84] with a feedback mechanism ([Fig. 4]). In ovarian cancer cell lines, curcumin regulates the DNA methylation status of genes by decreasing the expression of DNA methyltransferase 3A (DNMT3A) [85]. The inhibitory effect of curcumin on gastric cancer is mainly through direct binding to TETs via hydrogen bonding, which promotes the reactivation of TETs and thus increases the methylation level of the RB1 promoter [86]. [Table 1] summarizes the effects of curcumin on the methylation status of various tumors [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100].

Fig. 4 Curcumin promotes apoptosis of cancer cells through DNA methylation.

Table 1 Genes with altered methylation status by curcumin in tumors.

Type of Cancer	Genes	Mechanism of Action	References
Prostate Cancer	AR	AR promoter methylation level ↓; AR expression ↑	[87]
	NRF2	NRF2 promoter region − 1266 to − 1086 bp dimethylation level ↓; NRF2 expression ↑	[88]
	NEUROG1	NEUROG1 promoter methylation level ↓; NEUROG1 expression ↑	[89]
	CDX2	DNMT1 and DNMT3A ↓; CDX2 promoter methylation level ↓; CDX2 expression ↑	[90]
Colorectal Cancer	DLEC1	↓ expression of DNMT1 and TET1; ↑ expression of DNMT3A and DNMT3B.	[91]
	TNF	DNMT1 expression ↓ by downregulating transcription factor SP1; DLC1 promoter methylation level ↓; DLC1 expression ↑	[92]
	BRCA1	GSTP1 promoter methylation level ↓; GSTP1 expression ↑	[93]
	SNCG	DNMT1 ↓; RASSF1A promoter methylation level ↓; RASSF1A expression ↑	[94]
Lung Cancer	RARβ	Methylation status ↓; WIF-1 expression ↑	[95]
	WIF-1	RARβ promoter methylation level ↓; RARβ expression ↑	[96]
Gastric Cancer	RB1	Curcumin binds to TET2 and TET3 via hydrogen bonding, reactivating TETs and increasing RB1 promoter methylation levels ↓; RB1 expression ↑	[97]
Nephroblastoma	RECK	RECK promoter methylation level ↓; RECK expression ↑; resulting in MMP2 and MMP9 expression ↓	[98]
Ovarian Cancer	SFRP5	Reducing the expression of DNMT3A by inhibiting the activity of DNMTs leads to ↓ of SFRP5 methylation level and promotes the expression of SFRP5	[99]
Glioblastoma	RANK	NF-κB promoter methylation level ↓; NF-κB expression ↑	[100]

Affecting histone modifications

Histone-mediated post-translational modification (PTM) is an important chromatin modification mechanism that regulates gene expression, including acetylation, methylation, phosphorylation, and many other ways [101], [102], [103]. Abnormal histone modifications may lead to tumor or cancer development. Curcumin, as a natural compound, is able to regulate histone modification and thus inhibit tumor development through the following mechanisms: ability to induce acetylation and glutathionylation of histone H3, which inhibits the viability and proliferation of cancer cells [103], [104], [105], [106]; ability to silence EZH2 (Drosophila zeste gene human homolog of enhancer 2), restore expression of DLC1 (hepatocellular carcinoma deletion gene 1), and inhibit migration, invasion, and proliferation of triple-negative breast cancer cells [107]. It was able to reduce the mRNA level and protein concentration of PRMT5 (arginine methyltransferase 5) and inhibit cancer cell proliferation [108].

Influence on Non-Coding RNA Expression

miRNA

MicroRNAs (miRNAs) are a class of endogenous small ribonucleic acids about 20 – 24 nucleotides in length, which play a variety of important regulatory roles in cells. miRNAs regulate the expression of multiple genes through a complex regulatory network, either a single miRNA, or multiple miRNAs finely regulate the expression of a single gene [109], [110]. Many miRNAs function as oncogenes or tumor suppressors, and the dysregulation of their expression is closely related to the occurrence, development, and metastasis of cancer [111], [112].

Curcumin is able to regulate multiple molecular targets and signal transduction pathways by affecting miRNA expression, thereby inhibiting tumor progression. Specifically, curcumin can regulate the expression of proto-oncogenes (e.g., miR-19a and miR19b), as well as oncogenic miRNAs (e.g., miR-15a, miR-16, miR-34a, miR146b 5 p, and miR-181b) in breast cancer cells [113]. In addition, curcumin was able to influence tumor growth, invasion, and metastasis by inhibiting the transcription of miR-21 and stabilizing the expression of the colorectal cancer oncogene PDCD4 [114]. Curcumin also alters the distribution of miR-21 in the cytoplasm and exosomes of chronic granulocytic leukemia cells, decreasing miR-21 levels in the cytoplasm and promoting the expression of the target gene PTEN; elevated levels of miR-21 in the exosomes inhibit the expression of MARCKS, which collectively leads to the down-regulation of VEGF expression and maintenance of vascular integrity ([Fig. 5 a]) [115], [116]. Curcumin can also alter the DNA methylation status and affect gene expression, a mechanism also present in the regulation of miRNA expression. Studies have shown that curcumin can alter the methylation status of miRNA promoters in bladder cancer, promoting the expression of miR-203, which in turn inhibits the expression of downstream target genes ([Fig. 5 b]) [117]. Among the miRNAs affected by curcumin, such as miR-130a, miR-34a and miR-9 promoters are regulated by DNA methylation [118], [119], which implies that curcumin can participate in the expression of other miRNAs through the mechanism of DNA methylation to exert anti-cancer effects. The radiosensitizing effect of curcumin on tumor cells also relies on the regulation of miRNA expression, mainly including miR-186, miR-30c, miR-146a, miR-200c, miR-143, miR-145, miR-1246, and miR-124 [120], [121], [122], [123], [124], [125], [126]. Specifically, curcumin improved tumor sensitivity to chemotherapeutic agents by up-regulating the expression of miR-200c and targeted PRC, achieving chemosensitization to colorectal cancer [140]. This result links miRNAs to histone modifications, suggesting that curcumin is involved in the regulation of complex epigenetic mechanisms in exerting its anticancer effects. We summarize the reported miRNAs regulated by curcumin in [Table 2] [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153].

Fig. 5 Curcumin inhibits cancer cell growth via miRNA.

Table 2 Curcumin-regulated miRNAs in cancer.

Type of Cancer	miRNA	Mechanism of Action	References
Notes: ↓: Lower Expression; ↑: High Expression
Nasopharyngeal Carcinoma	miR-125a-5p	miR-125a-5p expression ↑, TP53 expression ↓	[127]
	miR-7	miR-7 expression ↑, SKP2 expression ↓, which in turn promotes p21 expression	[128]
Multiple myeloma	miR-101	miR-101 expression is ↑, EZH2 expression is ↓, and there is feedback regulation	[129]
	miR-206	miR-206 expression ↑, inhibits PI3K/AKT/mTOR pathway	[130]
Multiple myeloma Lung Cancer	miR-192 – 5 p	miR-192 – 5 p expression ↑, c-MYC expression ↓, and inhibition of Wnt/β-catenin signaling pathway	[131]
	miRNA-548ah-5p	miRNA-548ah-5p expression ↑, may promote apoptosis of cancer cells through cell cycle proteins, and by gene set variation variant analysis (GSVA) whose target genes may be CCNF, LOX1, MRGPRF and VEGF	[132]
	miR-98	miR-98 expression ↑, LIN28A, MMP2 and MMP9 expression ↓	[133]
	miR-330 – 5 p	miR-330 – 5 p expression↑	[134]
	miR-192 – 5 p,miR-215	Curcumin promotes miR-192 – 5 p, miR-215 expression ↑ through P53 and P21 expression, which in turn leads to XIAP ↓	[135]
Lung Cancer	miR-186	miR-186 expression was ↓, CASPASE-10 expression was ↑, while miR-186 expression was ↓ to achieve chemosensitization	[121], [135]
	miR-30c	miR-30c expression ↑, MTA1 expression ↓, chemosensitizing effect achieved	[121], [122]
	miR-192 – 5 p	miR-192 – 5 p expression ↑, inhibits PI3K/Akt signaling pathway	[136]
	miR-21	miR-21 expression ↓, PTEN expression ↑	[137]
Liver Cancer	miR-21 – 5 p	miR-21 – 5 p expression ↓, SOX6 expression ↑	[138]
	miR-19A	miR-19A expression ↑, CTGF expression ↓	[139]
Colorectal Cancer	miR-200c	Upregulation of miR-200c, which inhibits PRC (multiple comb inhibitory complex), leads to histone H3K27me3 and achieves chemosensitization	[140]
	miR-34a and miR-27a	miR-34a and miR-27a expression ↑	[141]
	miR-21	Blocked AP-1 binding to miR-21 promoter, resulting in ↓ miR-21 expression and promoting PDCD4 expression ↑	[114]
Prostate Cancer	miR-770 – 5 p and miR1247	Inhibition of prostate cancer cell growth by regulating the expression of specific miRNAs (miR-770 – 5 p and miR1247) in the DLK1-DIO3 imprinted gene cluster	[142]
	miR-143/miR-145 cluster	Induces autophagy by suppressing miRNA promoter methylation levels, leading to ↑ miR-143/miR-145 expression and achieve radiosensitization of prostate cancer	[124]
Breast Cancer	miR-142 – 3 p	Inhibition via p300/miR-142 – 3 p/PSMB5 axis and consequently 20S proteasome	[143]
	miR-34a	miR-34a expression ↑, AXL, SLUG, CD24, RHO-A expression ↓	[144]
	miR-34a	miR-15a and miR-16 expression ↑, BCL2 expression ↓	[145]
Pancreatic Cancer	miR-22	miRNA-22 expression ↑, SP1 and ESR1 expression ↓	[146]
	miR-7	miR-7 expression ↑, SET8 and LIF2 expression ↓	[147]
Ovarian Cancer	miR-9	miR-9 expression ↑, decreased AKT and FOXO1 phosphorylation	[148]
	miR-214	miR-214 expression ↓ for chemosensitization	[126]
Renal cell carcinoma	miR-106b-5p	miR-106b-5p expression ↓, p21 expression ↑	[149]
Esophageal Cancer	miR-21, miR-34a and let-7a	miR-21, miR-34a expression ↓, let-7a expression ↑	[150]
Gastric Cancer	miR-34a	miR-34a expression ↑, BCL2, CDK4 and cyclin D1 expression ↓	[151]
	miR-21	miR-21 expression ↓, PTEN expression ↑, and inhibition of AKT phosphorylation	[152]
	miR-33b	miR-33b expression ↑, XIAP expression ↓	[153]

lnc-RNA

Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules that play important roles in the nucleus or cytoplasm of cells, and they can regulate gene expression by binding to epigenetic proteins or as ceRNAs that competitively bind to microRNAs [154]. In a variety of tumors, aberrant expression of lncRNAs is closely associated with tumorigenesis, progression, and metastasis, with some lncRNAs promoting tumor progression while others suppress it [155], [156]. For example, LncRNA CASC9 is aberrantly expressed in a variety of malignant tumors, and its overexpression accelerates cell proliferation, invasion, and migration, enhances drug resistance of tumor cells, and inhibits apoptosis, similar to the role of oncogenes [157].

Curcumin exerts its inhibitory effect on lncRNAs in two ways: (i) regulating miRNAs through the ceRNA effect of lncRNAs and (ii) directly inhibiting the expression of tumor-associated lncRNAs (e.g., H19 and LncRNA-PVT1). It was shown that curcumin inhibited the expression of lncRNA-ROR while up-regulating miR-145 in human prostate cancer stem cells and inhibited the proliferation and in vitro invasion of human prostate cancer stem cells through the ceRNA effect of lncRNA-ROR and miR145 [46], and it was also shown that lncRNA-ROR could target binding to miR-185- 3 p, miR-26, and miR-206 and affect the growth of cancer cells [158], [159], [160]. Of course, in addition to exerting ceRNA effects, lncRNA-ROR appears to influence tumor development through other pathways, such as, for example, by inhibiting the growth of hepatocellular carcinoma cells through inactivation of the WNT pathway [161] and acting as a decoy molecule to recruit MLL1 methylation transferase, promote histone methylation of the TIMP3 gene H3K4, and induce breast cancer [152], and is significantly associated with multi-drug resistance in tumor cells [162] ([Fig. 6]). In addition, long-term radiotherapy and chemotherapy can lead to the tolerance of cancer cells. At the same time, curcumin can enhance or reverse cancer cellsʼ sensitivity to radiotherapy and chemotherapy by regulating the expression of lncRNA. Yoshida et al. used curcumin to inhibit the expression of EZH2 and lncRNA-PVT1 from reactivating the chemical sensitivity of drug-resistant cancer cells. This effect came from two aspects: (i) lncRNA-PVT1 can act as a protein complex scaffold to bind to PRC and affect histone modifications, and curcumin inhibited the expression of lncRNA-PVT1 to reduce PRC complex formation; (ii) EZH2 is an essential component of PRC subunits, and curcumin similarly reduced the protein level of EZH2 [163]. Another study showed that curcumin could up-regulate miR-101 and inhibit the translation of EZH2 through 3′UTR targeting [129]. Interestingly, other studies have confirmed that lncRNA-PVT1 can affect EZH2 expression by binding miRNA-526b [164]. There have been many reports on the cancer-inhibiting effects of curcumin, but studies involving the regulation of circRNA to inhibit the proliferation and migration of cancer cells are still rare. A recent study analyzed poor circRNA in radioresistant nasopharyngeal carcinoma cell lines treated with curcumin using high-volume circRNA microarray technology and showed that curcumin inhibits epidermal growth factor receptor (EGFR), transcriptional activator 3 (STAT3), and growth factor receptor binding protein 2 (GRB2) through a circRNA/miRNA/mRNA regulatory network (GRB2) to achieve radiosensitization of cancer cells [165], [166]. It has also been shown that curcumin can regulate non-small cell lung carcinogenesis by inhibiting the expression of circ-PRKCA, and this mechanism is dependent on the adsorption of circ-PRKCA on miR-384 [166]. We summarize the reported lncRNAs regulated by curcumin in [Table 3] [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174], [175], [176], [177].

Fig. 6 Curcumin inhibits cancer cell growth via lncRNA-ROR.

Table 3 Curcumin-regulated lncRNAs in cancer.

Type of Cancer	LncRNA	Mechanism of Action	References
Notes: ↓: Lower Expression; ↑: High Expression
Colorectal Cancer	LncRNA-NBR2	LncRNA-NBR2 expression ↑ through AMPK pathway inhibits cancer cell growth	[167]
	LncRNA-KCNQ1OT1	LncRNA-KCNQ1OT1 expression ↓, attenuating the ceRNA of LncRNA-KCNQ1OT1 on miR-497 effect, resulting in ↓ expression of BCL2 and achieving chemosensitization effect	[163]
Breast Cancer	H19	H19 expression ↓, inhibiting H19-induced cancer cell migration and invasion, achieving chemosensitization	[168]
Prostate Cancer	LncRNA-ROR	The ceRNA effect of cRNA-ROR on miR-145 leads to low expression of OCT4	[169]
Stomach Cancer	H19	Promoting p53 activation through c-MYC leading to H19 expression low expression	[170]
Lung Cancer	LncRNA-UCA1	LncRNA-UCA1 expression ↓, inhibits WNT and mTOR pathway	[171]
	lncRNA-MEG3	lncRNA-MEG3 expression ↑, promoting PTEN expression, achieving chemosensitization	[172]
Liver Cancer	LncRNA-ROR	LncRNA-ROR expression ↓, inhibition of Wnt/β-catenin pathway pathway	[161]
Glioma Glioma	H19	H19 and miR-675 expression ↓, regulated by negative feedback inhibition of glioma growth	[173]
Nasopharyngeal Carcinoma	LncRNA-AK294 004	This LncRNA can lower the expression of CCND1 gene through its 3′UTR to reduce its expression, and curcumin can lead to ↓ expression of LncRNAAK294004, promote CCND1 expression, and realize the sensitizing effect of radiotherapy	[174]
Renal cell Cancer	lncRNA-HOTAIR	lncRNA-HOTAIR expression ↓, inhibiting cancer cell migration migration	[170]

Novel Drug Delivery System for Curcumin

Researchers are developing a variety of novel delivery systems to enhance the antitumor efficacy and bioavailability of curcumin without increasing toxicity. Nanoparticles serve as carriers for continuous drug delivery and protect the active ingredient during transport, altering tissue distribution and drug clearance. They can be used for multiple routes of administration, such as oral, nasal, and intravenous, and can enhance drug bioavailability. For example, in a study by Kanai et al. [171], plasma levels of curcumin were significantly increased in healthy volunteers after oral administration of curcumin nanoparticles, indicating enhanced bioavailability. The curcumin nanoparticle formulations prepared by Bahare [172] were superior to curcumin in terms of activity, targeting selectivity, and bioavailability. Liposomes, consisting of a phospholipid bilayer shell and an aqueous core, are ideal carriers for encapsulating hydrophobic and hydrophilic compounds. Despite the low encapsulation rate (45%), curcumin liposomes showed 20-fold higher cytotoxicity than curcumin in a variety of cell lines. Different types of curcumin-loaded long-circulating liposomes prepared by Mahmud et al. [173] showed strong anticancer activity against human pancreatic adenocarcinoma AsPC-1 and BxPC-3 cells but were weakly toxic to normal cell lines. Biodegradable synthetic polymers (e.g., poly(lactide-co-glycolide) [PLGA]) and natural polymers (e.g., serine proteins and chitosan) have been widely used for drug delivery. Studies have shown that PLGA-curcumin is at least 15-fold more effective than natural curcumin in preventing blood–brain barrier disruption and inhibiting inflammatory cytokines [174]. Solid dispersion drug delivery has emerged as an efficient mode of delivery for administering efficacious but poorly water-soluble anticancer drugs. A rat study [179] found that the gastric bioavailability of curcumin from micellar solid dispersions was 19 times higher than that of free curcumin. Micelles are aqueous formulations that improve hydrophobic drugs, prolong drug circulation time in the body, increase cellular uptake, and target tumor regions. Zhang et al. [180] prepared novel nanomicelles (PPNMs) with up to a 96.7% encapsulation rate, which can control the release of curcumin precursor drugs through redox reactions.

Summary and Perspective

As a natural compound, curcumin can combat tumor development through a variety of mechanisms, including promoting apoptosis, modulating cellular autophagy, and influencing the NF-κB signaling pathway, and these mechanisms of action provide a deeper understanding of Curcuminʼs antitumor activity. It has also been shown to alter epigenetic mechanisms [181], which may lead to increased sensitivity of cancer cells to conventional drugs, thereby inhibiting tumor growth. This mechanism provides a new perspective on curcumin as a potential anticancer therapeutic agent. The combination of curcumin with other treatments such as PD-1/PD-L1 inhibitors shows novel therapeutic potential, which may provide new strategies for tumor treatment.

Although the antitumor effects of curcumin have been widely verified in in vitro experiments, its effects in vivo may be affected by a variety of factors, including bioavailability, metabolic stability, and the dose-effect relationship. Therefore, although curcumin showed antitumor activity in in vitro experiments, its in vivo effect and clinical application value still need to be verified by more in vivo studies and clinical trials. The antitumor potential of curcumin is worthy of further investigation, but its nature as a PAIN or IMP needs to be evaluated through rigorous scientific studies. PAINs may interfere with experimental readings by reacting with reagents, enzymes, or other proteins used in the experiments or by affecting intracellular signaling pathways. IMPs may interfere with experimental readings because they are unable to efficiently cross the cellular membrane and are in vivo because of their inability to cross cell membranes efficiently, because they are rapidly metabolized or excreted or because they are not present in the body in sufficient concentrations to produce a therapeutic effect. The identification and exclusion of PAINs and IMPs are important in drug research because they help to ensure the reliability of the results and the efficacy of the drug candidate. Researchers need to exclude these interfering factors through rigorous experimental design, controlled experiments, and validation experiments to ensure that the activity of the drug candidate is real and effective. Also, the multi-targeted mechanism of action of curcumin may lead to non-specific biological effects, which need to be attended to and controlled in research. Adverse effects of curcumin such as gastrointestinal reactions, contact dermatitis, hepatobiliary toxicity, and immunologic adverse events have also been reported in the literature [182].

In conclusion, curcumin, a traditional Chinese medicine extract, acts as an anticancer agent, chemosensitizer, and immunomodulator through various complex mechanisms. Compared with traditional chemotherapeutic agents, chemo-sensitizers, and immune checkpoint inhibitors, curcumin is widely available, inexpensive, and safe. It can be widely used as an antitumor prophylactic agent. However, its bioavailability is a key limiting factor for its use as a therapeutic agent and still requires further research; therefore, the development of curcumin derivatives or novel nanoformulations is crucial for improving the bioavailability of curcumin and enhancing its anticancer effects [183].

Search Strategy

1. Databases: PubMed, Web of Science, Embase, and Google Scholar English databases.

2. Search terms: curcumin was used as the core search term, and antitumor molecular mechanism, tumor immunity, epigenetics, drug delivery, drug delivery system were used as the related subject terms for the search.

3. Search method: use Boolean operators (AND, OR) to combine search terms, “curcumin AND (antitumor molecular mechanism OR epigenetics OR tumor immunity OR drug delivery OR drug delivery system)”.
   In PubMed, a precise search was performed using the MeSH vocabulary, using the MeSH term “Curcumin” in conjunction with the relevant subject terms described above.
   In Web of Science, the search was performed using subject terms and related subject headings, and the citation index was used to track related literature.
   In Embase, subject searches were conducted using the Emtree vocabulary and free words were used to extend the search.
   In Google Scholar, full-text searches were performed directly using combinations of search terms.

4. Search date: 2014.1.1 – 2024.6.30

5. Criteria for exclusion: exclude literature of lower quality and articles or preprints that have not been peer-reviewed. Exclude non-English literature.

Contributorsʼ Statement

Xin Wan designed the structure of the article and finished writing the paper as the first author. Dong Wangacted as corresponding author rearching the database and extracting literature, drawing the figures, all authors declare no conflict of interest.

Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Thanks to the editors and reviewers for their hard work and valuable comments.

• References

• 1 Global Burden of Disease Cancer Collaboration. Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, Abdelalim A, Abdoli A, Abdollahpour I, Abdulle ASM, Abebe ND, Abraha HN, Abu-Raddad LJ, Abualhasan A, Adedeji IA, Advani SM, Afarideh M, Afshari M, Aghaali M, … Murray CJL. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: A systematic analysis for the global burden of disease study. JAMA Oncol 2019; 5: 1749-1768
• 2 Global Burden of Disease 2019 Cancer Collaboration. Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, Henrikson HJ, Lu D, Pennini A, Xu R, Ababneh E, Abbasi-Kangevari M, Abbastabar H, Abd-Elsalam SM, Abdoli A, Abedi A, Abidi H, Abolhassani H, Adedeji IA, … Force LM. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: A systematic analysis for the global burden of disease study 2019. JAMA Oncol 2022; 8: 420-444
• 3 Sioka C. Radiotherapy, chemotherapy, and heart disease. Breast Cancer Res Treat 2022; 193: 239-240
• 4 Giordano A, Tommonaro G. Curcumin and Cancer. Nutrients 2019; 11: 2376
• 5 Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, Yang C. Curcumin as an alternative epigenetic modulator: Mechanism of action and potential effects. Front Genet 2019; 10: 514
• 6 Kumar G, Mittal S, Sak K, Tuli HS. Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives. Life Sci 2016; 148: 313-328
• 7 Choi H, Chun YS, Shin YJ, Ye SK, Kim MS, Park JW. Curcumin attenuates cytochrome P450 induction in response to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin by ROS-dependently degrading AhR and ARNT. Cancer Sci 2008; 99: 2518-2524
• 8 Garg R, Gupta S, Maru GB. Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis 2008; 29: 1022-1032
• 9 DʼArcy MS. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43: 582-592
• 10 Fu H, Wang C, Yang D, Wei Z, Xu J, Hu Z, Zhang Y, Wang W, Yan R, Cai Q. Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling. J Cell Physiol 2018; 233: 4634-4642
• 11 Li W, Zhou Y, Yang J, Li H, Zhang H, Zheng P. Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells. Oncol Rep 2017; 37: 3459-3466
• 12 Fratantonio D, Molonia MS, Bashllari R, Muscarà C, Ferlazzo G, Costa G, Saija A, Cimino F, Speciale A. Curcumin potentiates the antitumor activity of Paclitaxel in rat glioma C6 cells. Phytomedicine 2019; 55: 23-30
• 13 Sha J, Li J, Wang W, Pan L, Cheng J, Li L, Zhao H, Lin W. Curcumin induces G0/G1 arrest and apoptosis in hormone independent prostate cancer DU-145 cells by down regulating Notch signaling. Biomed Pharmacother 2016; 84: 177-184
• 14 Zheng R, Deng Q, Liu Y, Zhao P. Curcumin inhibits gastric carcinoma cell growth and induces apoptosis by suppressing the Wnt/β-catenin signaling pathway. Med Sci Monit 2017; 23: 163-171
• 15 Zhang L, Man S, Qiu H, Liu Z, Zhang M, Ma L, Gao W. Curcumin-cyclodextrin complexes enhanced the anti-cancer effects of curcumin. Environ Toxicol Pharmacol 2016; 48: 31-38
• 16 Yu X, Zhong J, Yan L, Li J, Wang H, Wen Y, Zhao Y. Curcumin exerts antitumor effects in retinoblastoma cells by regulating the JNK and p 38 MAPK pathways. Int J Mol Med 2016; 38: 861-868
• 17 Xu X, Zhu Y. Curcumin inhibits human non-small cell lung cancer xenografts by targeting STAT3 pathway. Am J Transl Res 2017; 9: 3633-3641
• 18 Liu WH, Yuan JB, Zhang F, Chang JX. [Curcumin inhibits proliferation, migration and invasion of gastric cancer cells via Wnt3a/β-catenin/EMT signaling pathway]. Zhongguo Zhong Yao Za Zhi 2019; 44: 3107-3115
• 19 Xu F, Ji Z, He L, Chen M, Chen H, Feng Q, Dong B, Yang X, Jiang L, Jin R. Downregulation of LINC01021 by curcumin analog Da0324 inhibits gastric cancer progression through activation of P53. Am J Transl Res 2020; 12: 3429-3444
• 20 Zhou X, Wang W, Li P, Zheng Z, Tu Y, Zhang Y, You T. Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in inducing gastric cancer cell apoptosis both in vitro and in vivo. Oncol Res 2016; 23: 29-34
• 21 Chen Q, Gao Q, Chen K, Wang Y, Chen L, Li XU. Curcumin suppresses migration and invasion of human endometrial carcinoma cells. Oncol Lett 2015; 10: 1297-1302
• 22 Liu X, Sun K, Song A, Zhang X, Zhang X, He X. Curcumin inhibits proliferation of gastric cancer cells by impairing ATP-sensitive potassium channel opening. World J Surg Oncol 2014; 12: 389
• 23 Cao A, Li Q, Yin P, Dong Y, Shi H, Wang L, Ji G, Xie J, Wu D. Curcumin induces apoptosis in human gastric carcinoma AGS cells and colon carcinoma HT-29 cells through mitochondrial dysfunction and endoplasmic reticulum stress. Apoptosis 2013; 18: 1391-1402
• 24 Moragoda L, Jaszewski R, Majumdar AP. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res 2001; 21: 873-878
• 25 Xu Y, Yu H, Qin H, Kang J, Yu C, Zhong J, Su J, Li H, Sun L. Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells. Cancer Lett 2012; 314: 232-243
• 26 Jin S, White E. Role of autophagy in cancer: Management of metabolic stress. Autophagy 2007; 3: 28-31
• 27 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274-293
• 28 Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: Therapeutic potential and persisting obstacles. Nat Rev Drug Discov 2017; 16: 487-511
• 29 You L, Jin S, Zhu L, Qian W. Autophagy, autophagy-associated adaptive immune responses and its role in hematologic malignancies. Oncotarget 2017; 8: 12374-12388
• 30 Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, Yang D, Yang A, Yu Y. Curcumin induced autophagy anticancer effects on human lung adenocarcinoma cell line A549. Oncol Lett 2017; 14: 2775-2782
• 31 Jia YL, Li J, Qin ZH, Liang ZQ. Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells. J Asian Nat Prod Res 2009; 11: 918-928
• 32 Moustapha A, Pérétout PA, Rainey NE, Sureau F, Geze M, Petit JM, Dewailly E, Slomianny C, Petit PX. Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events. Cell Death Discov 2015; 1: 15017
• 33 Kim JY, Cho TJ, Woo BH, Choi KU, Lee CH, Ryu MH, Park HR. Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells. Arch Oral Biol 2012; 57: 1018-1025
• 34 Pramanik KC, Makena MR, Bhowmick K, Pandey MK. Advancement of NF-κB signaling pathway: A novel target in pancreatic cancer. Int J Mol Sci 2018; 19: 3890
• 35 Vallée A, Lecarpentier Y, Vallée JN. Curcumin: A therapeutic strategy in cancers by inhibiting the canonical WNT/β-catenin pathway. J Exp Clin Cancer Res 2019; 38: 323
• 36 Ghasemi F, Shafiee M, Banikazemi Z, Pourhanifeh MH, Khanbabaei H, Shamshirian A, Amiri Moghadam S, ArefNezhad R, Sahebkar A, Avan A, Mirzaei H. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol Res Pract 2019; 215: 152556
• 37 Coker-Gurkan A, Celik M, Ugur M, Arisan ED, Obakan-Yerlikaya P, Durdu ZB, Palavan-Unsal N. Curcumin inhibits autocrine growth hormone-mediated invasion and metastasis by targeting NF-κB signaling and polyamine metabolism in breast cancer cells. Amino Acids 2018; 50: 1045-1069
• 38 Wang M, Jiang S, Zhou L, Yu F, Ding H, Li P, Zhou M, Wang K. Potential mechanisms of action of curcumin for cancer prevention: Focus on cellular signaling pathways and miRNAs. Int J Biol Sci 2019; 15: 1200-1214
• 39 Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell 2019; 176: 1248-1264
• 40 Fan S, Xu Y, Li X, Tie L, Pan Y, Li X. Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: in silico, in vitro and in vivo studies. Biochim Biophys Acta 2014; 1842: 1742-1754
• 41 Nagaraju GP, Zhu S, Ko JE, Ashritha N, Kandimalla R, Snyder JP, Shoji M, El-Rayes BF. Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. Cancer Lett 2015; 357: 557-565
• 42 Fan S, Xu Y, Li X, Tie L, Pan Y, Li X. Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: in silico, in vitro and in vivo studies. Biochim Biophys Acta 2014; 1842: 1742-1754
• 43 Wang S, Zhang Y. HMGB1 in inflammation and cancer. J Hematol Oncol 2020; 13: 116
• 44 Chhipa AS, Borse SP, Baksi R, Lalotra S, Nivsarkar M. Targeting receptors of advanced glycation end products (RAGE): Preventing diabetes induced cancer and diabetic complications. Pathol Res Pract 2019; 215: 152643
• 45 Da W, Zhang J, Zhang R, Zhu J. Curcumin inhibits the lymphangiogenesis of gastric cancer cells by inhibition of HMGB1/VEGF-D signaling. Int J Immunopathol Pharmacol 2019; 33: 2058738419861600
• 46 Da W, Zhu J, Wang L, Sun Q. Curcumin suppresses lymphatic vessel density in an in vivo human gastric cancer model. Tumour Biol 2015; 36: 5215-5223
• 47 Afrin R, Arumugam S, Rahman A, Wahed MI, Karuppagounder V, Harima M, Suzuki H, Miyashita S, Suzuki K, Yoneyama H, Ueno K, Watanabe K. Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation. Int Immunopharmacol 2017; 44: 174-182
• 48 Kanakkanthara A, Miller JH. βIII-tubulin overexpression in cancer: Causes, consequences, and potential therapies. Biochim Biophys Acta Rev Cancer 2021; 1876: 188607
• 49 Lopes D, Maiato H. The tubulin code in mitosis and cancer. Cells 2020; 9: 2356
• 50 Chakraborti S, Das L, Kapoor N, Das A, Dwivedi V, Poddar A, Chakraborti G, Janik M, Basu G, Panda D, Chakrabarti P, Surolia A, Bhattacharyya B. Curcumin recognizes a unique binding site of tubulin. J Med Chem 2011; 54: 6183-6196
• 51 Ando Y, Mariano C, Shen K. Engineered in vitro tumor models for cell-based immunotherapy. Acta Biomater 2021; 132: 345-359
• 52 Sloas C, Gill S, Klichinsky M. Engineered CAR-macrophages as adoptive immunotherapies for solid tumors. Front Immunol 2021; 12: 783305
• 53 Mukherjee S, Fried A, Hussaini R, White R, Baidoo J, Yalamanchi S, Banerjee P. Phytosomal curcumin causes natural killer cell-dependent repolarization of glioblastoma (GBM) tumor-associated microglia/macrophages and elimination of GBM and GBM stem cells. J Exp Clin Cancer Res 2018; 37: 168
• 54 Zhang HG, Kim H, Liu C, Yu S, Wang J, Grizzle WE, Kimberly RP, Barnes S. Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity. Biochim Biophys Acta 2007; 1773: 1116-1123
• 55 Mukherjee S, Hussaini R, White R, Atwi D, Fried A, Sampat S, Piao L, Pan Q, Banerjee P. TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors. Cancer Immunol Immunother 2018; 67: 761-774
• 56 Zheng P, Ding B, Jiang Z, Xu W, Li G, Ding J, Chen X. Ultrasound-augmented mitochondrial calcium ion overload by calcium nanomodulator to induce immunogenic cell death. Nano Lett 2021; 21: 2088-2093
• 57 Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res 2017; 27: 109-118
• 58 Varalakshmi CH, Ali AM, Pardhasaradhi BV, Srivastava RM, Singh S, Khar A. Immunomodulatory effects of curcumin: In-vivo. Int Immunopharmacol 2008; 8: 688-700
• 59 Bhattacharyya S, Md Sakib Hossain D, Mohanty S, Sankar Sen G, Chattopadhyay S, Banerjee S, Chakraborty J, Das K, Sarkar D, Das T, Sa G. Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell Mol Immunol 2010; 7: 306-315
• 60 Zhao GJ, Lu ZQ, Tang LM, Wu ZS, Wang DW, Zheng JY, Qiu QM. Curcumin inhibits suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. Int Immunopharmacol 2012; 14: 99-106
• 61 Bhattacharyya S, Mandal D, Saha B, Sen GS, Das T, Sa G. Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction. J Biol Chem 2007; 282: 15954-15964
• 62 Lv J, Shao Q, Wang H, Shi H, Wang T, Gao W, Song B, Zheng G, Kong B, Qu X. Effects and mechanisms of curcumin and basil polysaccharide on the invasion of SKOV3 cells and dendritic cells. Mol Med Rep 2013; 8: 1580-1586
• 63 Jeong YI, Kim SW, Jung ID, Lee JS, Chang JH, Lee CM, Chun SH, Yoon MS, Kim GT, Ryu SW, Kim JS, Shin YK, Lee WS, Shin HK, Lee JD, Park YM. Curcumin suppresses the induction of indoleamine 2, 3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. J Biol Chem 2009; 284: 3700-3708
• 64 Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, Chang SS, Lin WC, Hsu JM, Hsu YH, Kim T, Chang WC, Hsu JL, Yamaguchi H, Ding Q, Wang Y, Yang Y, Chen CH, Sahin AA, Yu D, Hortobagyi GN, Hung MC. Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell 2016; 30: 925-939
• 65 Guo L, Li H, Fan T, Ma Y, Wang L. Synergistic efficacy of curcumin and anti-programmed cell death-1 in hepatocellular carcinoma. Life Sci 2021; 279: 119359
• 66 Dent P, Booth L, Roberts JL, Poklepovic A, Hancock JF. (Curcumin+sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo. J Cell Physiol 2020; 235: 6862-6874
• 67 Dai L, Li X, Yao M, Niu P, Yuan X, Li K, Chen M, Fu Z, Duan X, Liu H, Cai K, Yang H. Programmable prodrug micelle with size-shrinkage and charge-reversal for chemotherapy-improved IDO immunotherapy. Biomaterials 2020; 241: 119901
• 68 Chang YF, Chuang HY, Hsu CH, Liu RS, Gambhir SS, Hwang JJ. Immunomodulation of curcumin on adoptive therapy with T cell functional imaging in mice. Cancer Prev Res (Phila) 2012; 5: 444-452
• 69 Lu Y, Miao L, Wang Y, Xu Z, Zhao Y, Shen Y, Xiang G, Huang L. Curcumin micelles remodel tumor microenvironment and enhance vaccine activity in an advanced melanoma model. Mol Ther 2016; 24: 364-374
• 70 Jiang GM, Xie WY, Wang HS, Du J, Wu BP, Xu W, Liu HF, Xiao P, Liu ZG, Li HY, Liu SQ, Yin WJ, Zhang QG, Liang JP, Huang HJ. Curcumin combined with FAPαc vaccine elicits effective antitumor response by targeting indolamine-2, 3-dioxygenase and inhibiting EMT induced by TNF-α in melanoma. Oncotarget 2015; 6: 25932-25942
• 71 Liu X, Feng Z, Wang C, Su Q, Song H, Zhang C, Huang P, Liang XJ, Dong A, Kong D, Wang W. Co-localized delivery of nanomedicine and nanovaccine augments the postoperative cancer immunotherapy by amplifying T-cell responses. Biomaterials 2020; 230: 119649
• 72 Jensen NF, Stenvang J, Beck MK, Hanáková B, Belling KC, Do KN, Viuff B, Nygård SB, Gupta R, Rasmussen MH, Tarpgaard LS, Hansen TP, Budinská E, Pfeiffer P, Bosman F, Tejpar S, Roth A, Delorenzi M, Andersen CL, Rømer MU, Brünner N, Moreira JM. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol Oncol 2015; 9: 1169-1185
• 73 Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, Shakibaei M, Boland CR, Goel A. Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis 2015; 36: 355-367
• 74 Zhang C, Xu Y, Wang H, Li G, Yan H, Fei Z, Xu Y, Li W. Curcumin reverses irinotecan resistance in colon cancer cell by regulation of epithelial-mesenchymal transition. Anticancer Drugs 2018; 29: 334-340
• 75 Su P, Yang Y, Wang G, Chen X, Ju Y. Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells. Int J Oncol 2018; 53: 1343-1353
• 76 Firouzi Amoodizaj F, Baghaeifar S, Taheri E, Farhoudi Sefidan Jadid M, Safi M, Seyyed Sani N, Hajazimian S, Isazadeh A, Shanehbandi D. Enhanced anticancer potency of doxorubicin in combination with curcumin in gastric adenocarcinoma. J Biochem Mol Toxicol 2020; 34: e22486
• 77 Yu LL, Wu JG, Dai N, Yu HG, Si JM. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor. Oncol Rep 2011; 26: 1197-1203
• 78 Li F, Chen X, Xu B, Zhou H. Curcumin induces p 53-independent necrosis in H1299 cells via a mitochondria-associated pathway. Mol Med Rep 2015; 12: 7806-7814
• 79 Zafon C, Gil J, Pérez-González B, Jordà M. DNA methylation in thyroid cancer. Endocr Relat Cancer 2019; 26: R415-R439
• 80 Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet 2021; 37: 1012-1027
• 81 Choi SJ, Jung SW, Huh S, Chung YS, Cho H, Kang H. Alteration of DNA methylation in gastric cancer with chemotherapy. J Microbiol Biotechnol 2017; 27: 1367-1378
• 82 Schübeler D. Function and information content of DNA methylation. Nature 2015; 517: 321-326
• 83 Tong R, Wu X, Liu Y, Liu Y, Zhou J, Jiang X, Zhang L, He X, Ma L. Curcumin-induced DNA Demethylation in human gastric cancer cells is mediated by the DNA-damage response pathway. Oxid Med Cell Longev 2020; 2020: 2543504
• 84 Chatterjee B, Ghosh K, Kanade SR. Curcumin-mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p 21Cip1 in vitro. J Cell Biochem 2019; 120: 809-820
• 85 Yen HY, Tsao CW, Lin YW, Kuo CC, Tsao CH, Liu CY. Regulation of carcinogenesis and modulation through Wnt/β-catenin signaling by curcumin in an ovarian cancer cell line. Sci Rep 2019; 9: 17267
• 86 Cao D, Jia Z, Wu Y, Su T, Zhao D, Wu M, Tsukamoto T, Oshima M, Jiang J, Cao X. Demethylation of the RB1 promoter concomitant with reactivation of TET2 and TET3 impairs gastric carcinogenesis in K19-Wnt1/C2 mE transgenic mice. Life Sci 2020; 263: 118580
• 87 Sharma V, Kumar L, Mohanty SK, Maikhuri JP, Rajender S, Gupta G. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor – Synergistic action of quercetin and curcumin. Mol Cell Endocrinol 2016; 431: 12-23
• 88 Khor TO, Huang Y, Wu TY, Shu L, Lee J, Kong AN. Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. Biochem Pharmacol 2011; 82: 1073-1078
• 89 Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY, Saw CL, Cheung KL, Kong AN. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J 2011; 13: 606-614
• 90 Chen T, Yang C, Xi Z, Chen F, Li H. Reduced caudal type homeobox 2 (CDX2) promoter methylation is associated with curcuminʼs suppressive effects on epithelial-mesenchymal transition in colorectal cancer cells. Med Sci Monit 2020; 26: e926443
• 91 Guo Y, Shu L, Zhang C, Su ZY, Kong AN. Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochem Pharmacol 2015; 94: 69-78
• 92 Guo Y, Wu R, Gaspar JM, Sargsyan D, Su ZY, Zhang C, Gao L, Cheng D, Li W, Wang C, Yin R, Fang M, Verzi MP, Hart RP, Kong AN. DNA methylome and transcriptome alterations and cancer prevention by curcumin in colitis-accelerated colon cancer in mice. Carcinogenesis 2018; 39: 669-680
• 93 Al-Yousef N, Shinwari Z, Al-Shahrani B, Al-Showimi M, Al-Moghrabi N. Curcumin induces re-expression of BRCA1 and suppression of γ synuclein by modulating DNA promoter methylation in breast cancer cell lines. Oncol Rep 2020; 43: 827-838
• 94 Liu Y, Zhou J, Hu Y, Wang J, Yuan C. Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter. Mol Cell Biochem 2017; 425: 47-58
• 95 Kumar U, Sharma U, Rathi G. Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line. Tumour Biol 2017; 39: 1010428317692258
• 96 Du L, Xie Z, Wu LC, Chiu M, Lin J, Chan KK, Liu S, Liu Z. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Cancer 2012; 64: 1228-1235
• 97 Jiang A, Wang X, Shan X, Li Y, Wang P, Jiang P, Feng Q. Curcumin reactivates silenced tumor suppressor gene RARβ by reducing DNA methylation. Phytother Res 2015; 29: 1237-1245
• 98 Liu YL, Yang HP, Gong L, Tang CL, Wang HJ. Hypomethylation effects of curcumin, demethoxycurcumin and bisdemethoxycurcumin on WIF-1 promoter in non-small cell lung cancer cell lines. Mol Med Rep 2011; 4: 675-679
• 99 Jha AK, Nikbakht M, Parashar G, Shrivastava A, Capalash N, Kaur J. Reversal of hypermethylation and reactivation of the RARβ2 gene by natural compounds in cervical cancer cell lines. Folia Biol (Praha) 2010; 56: 195-200
• 100 Jia W, Deng F, Fu W, Hu J, Chen G, Gao X, Tan X, Li G, Liu G, Zhu S. Curcumin suppresses Wilmsʼ tumor metastasis by inhibiting RECK methylation. Biomed Pharmacother 2019; 111: 1204-1212
• 101 Wei X, Yi X, Zhu XH, Jiang DS. Posttranslational modifications in ferroptosis. Oxid Med Cell Longev 2020; 2020: 8832043
• 102 Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring Harb Perspect Biol 2016; 8: a019521
• 103 Soflaei SS, Momtazi-Borojeni AA, Majeed M, Derosa G, Maffioli P, Sahebkar A. Curcumin: A natural pan-HDAC inhibitor in cancer. Curr Pharm Des 2018; 24: 123-129
• 104 Cianfruglia L, Minnelli C, Laudadio E, Scirè A, Armeni T. Side effects of curcumin: Epigenetic and antiproliferative implications for normal dermal fibroblast and breast cancer cells. Antioxidants (Basel) 2019; 8: 382
• 105 Guccione E, Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol 2019; 20: 642-657
• 106 Tan YT, Lin JF, Li T, Li JJ, Xu RH, Ju HQ. LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer,. Cancer Commun (Lond) 2021; 41: 109-120
• 107 Zhou X, Jiao D, Dou M, Zhang W, Lv L, Chen J, Li L, Wang L, Han X. Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression. J Cell Mol Med 2020; 24: 10648-10662
• 108 Chatterjee B, Ghosh K, Suresh L, Kanade SR. Curcumin ameliorates PRMT5-MEP50 arginine methyltransferase expression by decreasing the Sp1 and NF-YA transcription factors in the A549 and MCF-7 cells. Mol Cell Biochem 2019; 455: 73-90
• 109 Lu TX, Rothenberg ME. MicroRNA. J Allergy Clin Immunol 2018; 141: 1202-1207
• 110 Eniafe J, Jiang S. MicroRNA-99 family in cancer and immunity. Wiley Interdiscip Rev RNA 2021; 12: e1635
• 111 Hill M, Tran N. miRNA interplay: Mechanisms and consequences in cancer. Dis Model Mech 2021; 14: dmm047662
• 112 Tutar Y. miRNA and cancer; computational and experimental approaches. Curr Pharm Biotechnol 2014; 15: 429
• 113 Norouzi S, Majeed M, Pirro M, Generali D, Sahebkar A. Curcumin as an adjunct therapy and microRNA modulator in breast cancer. Curr Pharm Des 2018; 24: 171-177
• 114 Mudduluru G, George-William JN, Muppala S, Asangani IA, Kumarswamy R, Nelson LD, Allgayer H. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep 2011; 31: 185-197
• 115 Taverna S, Giallombardo M, Pucci M, Flugy A, Manno M, Raccosta S, Rolfo C, De Leo G, Alessandro R. Curcumin inhibits in vitro and in vivo chronic myelogenous leukemia cells growth: A possible role for exosomal disposal of miR-21. Oncotarget 2015; 6: 21918-21933
• 116 Taverna S, Fontana S, Monteleone F, Pucci M, Saieva L, De Caro V, Cardinale VG, Giallombardo M, Vicario E, Rolfo C, Leo GD, Alessandro R. Curcumin modulates chronic myelogenous leukemia exosomes composition and affects angiogenic phenotype via exosomal miR-21. Oncotarget 2016; 7: 30420-30439
• 117 Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, Yamamura S, Ueno K, Dahiya R. Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res (Phila) 2011; 4: 1698-1709
• 118 Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW. miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer. PLoS One 2013; 8: e54398
• 119 Peng H, Dong JY, Zhao YN, Wu WB, Yang XL, Chen D, Hu KF, Chen LH, Liu J. [The effect of methylation level of microRNA promoter on the expression of microRNAs and on the proliferation, migration and invasion of lung cancer cells]. Sichuan Da Xue Xue Bao Yi Xue Ban 2019; 50: 182-187
• 120 Zhang J, Zhang T, Ti X, Shi J, Wu C, Ren X, Yin H. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway. Biochem Biophys Res Commun 2010; 399: 1-6
• 121 Zhang J, Du Y, Wu C, Ren X, Ti X, Shi J, Zhao F, Yin H. Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186* signaling pathway. Oncol Rep 2010; 24: 1217-1223
• 122 Lu Y, Wang J, Liu L, Yu L, Zhao N, Zhou X, Lu X. Curcumin increases the sensitivity of Paclitaxel-resistant NSCLC cells to Paclitaxel through microRNA-30c-mediated MTA1 reduction. Tumour Biol 2017; 39: 1010428317698353
• 123 Wu H, Liu Q, Cai T, Chen YD, Wang ZF. Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma. Mol Med Rep 2015; 12: 5461-5466
• 124 Liu J, Li M, Wang Y, Luo J. Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition. J Drug Target 2017; 25: 645-652
• 125 Xu R, Li H, Wu S, Qu J, Yuan H, Zhou Y, Lu Q. MicroRNA-1246 regulates the radio-sensitizing effect of curcumin in bladder cancer cells via activating P53. Int Urol Nephrol 2019; 51: 1771-1779
• 126 Zhang J, Liu J, Xu X, Li L. Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer. Cancer Chemother Pharmacol 2017; 79: 479-487
• 127 Gao W, Chan JYW, Wong TS. Curcumin exerts inhibitory effects on undifferentiated nasopharyngeal carcinoma by inhibiting the expression of miR-125a-5 p. Clin Sci (Lond) 2014; 127: 571-579
• 128 Feng S, Wang Y, Zhang R, Yang G, Liang Z, Wang Z, Zhang G. Curcumin exerts its antitumor activity through regulation of miR-7/Skp2/p 21 in nasopharyngeal carcinoma cells. Onco Targets Ther 2017; 10: 2377-2388
• 129 Wu C, Ruan T, Liu W, Zhu X, Pan J, Lu W, Yan C, Tao K, Zhang W, Zhang C. Effect and mechanism of curcumin on EZH2 – miR-101 regulatory feedback loop in multiple myeloma. Curr Pharm Des 2018; 24: 564-575
• 130 Wang N, Feng T, Liu X, Liu Q. Curcumin inhibits migration and invasion of non-small cell lung cancer cells through up-regulation of miR-206 and suppression of PI3K/AKT/mTOR signaling pathway. Acta Pharm 2020; 70: 399-409
• 131 Pan Y, Sun Y, Liu Z, Zhang C. miR-192-5 p upregulation mediates the suppression of curcumin in human NSCLC cell proliferation, migration and invasion by targeting c-Myc and inactivating the Wnt/β-catenin signaling pathway. Mol Med Rep 2020; 22: 1594-1604
• 132 Mo F, Xiao Y, Zeng H, Fan D, Song J, Liu X, Luo M, Ma X. Curcumin-induced global profiling of transcriptomes in small cell lung cancer cells. Front Cell Dev Biol 2020; 8: 588299
• 133 Liu WL, Chang JM, Chong IW, Hung YL, Chen YH, Huang WT, Kuo HF, Hsieh CC, Liu PL. Curcumin inhibits LIN-28A through the activation of miRNA-98 in the lung cancer cell line A549. Molecules 2017; 22: 929
• 134 Zhan JW, Jiao DM, Wang Y, Song J, Wu JH, Wu LJ, Chen QY, Ma SL. Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion. Thorac Cancer 2017; 8: 461-470
• 135 Ye M, Zhang J, Zhang J, Miao Q, Yao L, Zhang J. Curcumin promotes apoptosis by activating the p 53-miR-192–5 p/215-XIAP pathway in non-small cell lung cancer. Cancer Lett 2015; 357: 196-205
• 136 Jin H, Qiao F, Wang Y, Xu Y, Shang Y. Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192–5 p and suppression of PI3K/Akt signaling pathway. Oncol Rep 2015; 34: 2782-2789
• 137 Zhang W, Bai W, Zhang W. MiR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells. Clin Transl Oncol 2014; 16: 708-713
• 138 Zhou C, Hu C, Wang B, Fan S, Jin W. Curcumin suppresses cell proliferation, migration, and invasion through modulating miR-21–5 p/SOX6 axis in hepatocellular carcinoma. Cancer Biother Radiopharm 2020; 3734
• 139 Zeng Y, Shen Z, Gu W, Wu M. Inhibition of hepatocellular carcinoma tumorigenesis by curcumin may be associated with CDKN1A and CTGF. Gene 2018; 651: 183-193
• 140 Wang H, Cai X, Ma L. Curcumin modifies epithelial-mesenchymal transition in colorectal cancer through regulation of miR-200c/EPM5. Cancer Manag Res 2020; 12: 9405-9415
• 141 Li B, Shi C, Li B, Zhao JM, Wang L. The effects of Curcumin on HCT-116 cells proliferation and apoptosis via the miR-491/PEG10 pathway. J Cell Biochem 2018; 119: 3091-3098
• 142 Zhu M, Zheng Z, Huang J, Ma X, Huang C, Wu R, Li X, Liang Z, Deng F, Wu J, Geng S, Xie C, Zhong C. Modulation of miR-34a in curcumin-induced antiproliferation of prostate cancer cells. J Cell Biochem 2019; 120: 15616-15624
• 143 Liu L, Fu Y, Zheng Y, Ma M, Wang C. Curcumin inhibits proteasome activity in triple-negative breast cancer cells through regulating p 300/miR-142–3 p/PSMB5 axis. Phytomedicine 2020; 78: 153312
• 144 Gallardo M, Kemmerling U, Aguayo F, Bleak TC, Muñoz JP, Calaf GM. Curcumin rescues breast cells from epithelial-mesenchymal transition and invasion induced by anti-miR-34a. Int J Oncol 2020; 56: 480-493
• 145 Yang J, Cao Y, Sun J, Zhang Y. Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells. Med Oncol 2010; 27: 1114-1118
• 146 Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther 2008; 7: 464-473
• 147 Bi Y, Shen W, Min M, Liu Y. MicroRNA-7 functions as a tumor-suppressor gene by regulating ILF2 in pancreatic carcinoma. Int J Mol Med 2017; 39: 900-906
• 148 Zhao SF, Zhang X, Zhang XJ, Shi XQ, Yu ZJ, Kan QC. Induction of microRNA-9 mediates cytotoxicity of curcumin against SKOV3 ovarian cancer cells. Asian Pac J Cancer Prev 2014; 15: 3363-3368
• 149 Sun K, Jia Z, Duan R, Yan Z, Jin Z, Yan L, Li Q, Yang J. Long non-coding RNA XIST regulates miR-106b-5 p/P21 axis to suppress tumor progression in renal cell carcinoma. Biochem Biophys Res Commun 2019; 510: 416-420
• 150 Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, Sharma P. Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS One 2012; 7: e30590
• 151 Sun C, Zhang S, Liu C, Liu X. Curcumin promoted miR-34a expression and suppressed proliferation of gastric cancer cells. Cancer Biother Radiopharm 2019; 34: 634-641
• 152 Qiang Z, Meng L, Yi C, Yu L, Chen W, Sha W. Curcumin regulates the miR-21/PTEN/Akt pathway and acts in synergy with PD98059 to induce apoptosis of human gastric cancer MGC-803 cells. J Int Med Res 2019; 47: 1288-1297
• 153 Sun Q, Zhang W, Guo Y, Li Z, Chen X, Wang Y, Du Y, Zang W, Zhao G. Curcumin inhibits cell growth and induces cell apoptosis through upregulation of miR-33b in gastric cancer. Tumour Biol 2016; 37: 13177-13184
• 154 Zhang X, Wang W, Zhu W, Dong J, Cheng Y, Yin Z, Shen F. Mechanisms and functions of long non-coding RNAs at multiple regulatory levels. Int J Mol Sci 2019; 20: 5573
• 155 Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B. Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer. Int J Mol Sci 2019; 20: 5758
• 156 Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: A new paradigm. Cancer Res 2017; 77: 3965-3981
• 157 Qi Y, Song C, Zhang J, Guo C, Yuan C. Oncogenic LncRNA CASC9 in cancer progression. Curr Pharm Des 2021; 27: 575-582
• 158 Wang W, Li Y, Zhi S, Li J, Miao J, Ding Z, Peng Y, Huang Y, Zheng R, Yu H, Qi P, Wang J, Fu X, Hu M, Chen S. LncRNA-ROR/microRNA-185-3 p/YAP1 axis exerts function in biological characteristics of osteosarcoma cells. Genomics 2021; 113: 450-461
• 159 Qin WW, Xin ZL, Wang HQ, Wang KP, Li XY, Wang X. Inhibiting lncRNA ROR suppresses growth, migration and angiogenesis in microvascular endothelial cells by up-regulating miR-26. Eur Rev Med Pharmacol Sci 2018; 22: 7985-7993
• 160 Fei D, Sui G, Lu Y, Tan L, Dongxu Z, Zhang K. The long non-coding RNA-ROR promotes osteosarcoma progression by targeting miR-206. J Cell Mol Med 2019; 23: 1865-1872
• 161 Shao J, Shi CJ, Li Y, Zhang FW, Pan FF, Fu WM, Zhang JF. LincROR mediates the suppressive effects of curcumin on hepatocellular carcinoma through inactivating Wnt/β-catenin signaling. Front Pharmacol 2020; 11: 847
• 162 Wang S, Chen W, Yu H, Song Z, Li Q, Shen X, Wu Y, Zhu L, Ma Q, Xing D. lncRNA ROR promotes gastric cancer drug resistance. Cancer Control 2020; 27: 1073274820904694
• 163 Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis 2017; 38: 1036-1046
• 164 Qiu C, Li S, Sun D, Yang S. lncRNA PVT1 accelerates progression of non-small cell lung cancer via targeting miRNA-526b/EZH2 regulatory loop. Oncol Lett 2020; 19: 1267-1272
• 165 Yang J, Zhu D, Liu S, Shao M, Liu Y, Li A, Lv Y, Huang M, Lou D, Fan Q. Curcumin enhances radiosensitization of nasopharyngeal carcinoma by regulating circRNA network. Mol Carcinog 2020; 59: 202-214
• 166 Xu X, Zhang X, Zhang Y, Wang Z. Curcumin suppresses the malignancy of non-small cell lung cancer by modulating the circ-PRKCA/miR-384/ITGB1 pathway. Biomed Pharmacother 2021; 138: 111439
• 167 Yu H, Xie Y, Zhou Z, Wu Z, Dai X, Xu B. Curcumin regulates the progression of colorectal cancer via LncRNA NBR2/AMPK pathway. Technol Cancer Res Treat 2019; 18: 1533033819870781
• 168 Cai J, Sun H, Zheng B, Xie M, Xu C, Zhang G, Huang X, Zhuang J. Curcumin attenuates lncRNA H19-induced epithelial-mesenchymal transition in tamoxifen-resistant breast cancer cells. Mol Med Rep 2021; 23: 13
• 169 Liu T, Chi H, Chen J, Chen C, Huang Y, Xi H, Xue J, Si Y. Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR. Gene 2017; 631: 29-38
• 170 Liu G, Xiang T, Wu QF, Wang WX. Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19. Oncol Lett 2016; 12: 5156-5162
• 171 Wang WH, Chen J, Zhang BR, Lu SJ, Wang F, Peng L, Dai JH, Sun YZ. Curcumin inhibits proliferation and enhances apoptosis in A549 cells by downregulating lncRNA UCA1. Pharmazie 2018; 73: 402-407
• 172 Gao L, Shao T, Zheng W, Ding J. Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer by regulating lncRNA-MEG3 and PTEN signaling. Clin Transl Oncol 2021; 23: 1386-1393
• 173 Pan JX, Chen TN, Ma K, Wang S, Yang CY, Cui GY. A negative feedback loop of H19/miR-675/VDR mediates therapeutic effect of cucurmin in the treatment of glioma. J Cell Physiol 2020; 235: 2171-2182
• 174 Wang Q, Fan H, Liu Y, Yin Z, Cai H, Liu J, Wang Z, Shao M, Sun X, Diao J, Liu Y, Tong L, Fan Q. Curcumin enhances the radiosensitivity in nasopharyngeal carcinoma cells involving the reversal of differentially expressed long non-coding RNAs. Int J Oncol 2014; 44: 858-864
• 175 Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K, Matsumoto S, Ishiguro H, Chiba T. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol 2012; 69: 65-70
• 176 Salehi B, Del Prado-Audelo ML, Cortés H, Leyva-Gómez G, Stojanović-Radić Z, Singh YD, Patra JK, Das G, Martins N, Martorell M, Sharifi-Rad M, Cho WC, Sharifi-Rad J. Therapeutic applications of curcumin nanomedicine formulations in cardiovascular diseases. J Clin Med 2020; 9: 746
• 177 Mahmud M, Piwoni A, Filipczak N, Janicka M, Gubernator J. Long-circulating curcumin-loaded liposome formulations with high incorporation efficiency, stability and anticancer activity towards pancreatic adenocarcinoma cell lines in vitro. PLoS One 2016; 11: e0167787
• 178 Dende C, Meena J, Nagarajan P, Nagaraj VA, Panda AK, Padmanaban G. Nanocurcumin is superior to native curcumin in preventing degenerative changes in experimental cerebral malaria. Sci Rep 2017; 7: 10062
• 179 Chen C, Huang X, Cai H, Xu J. Anti-proliferation and anti-angiogenesis of curcumin-K30 solid dispersion. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2010; 35: 1029-1036
• 180 Zhang HY, Sun CY, Adu-Frimpong M, Yu JN, Xu XM. Glutathione-sensitive PEGylated curcumin prodrug nanomicelles: Preparation, characterization, cellular uptake and bioavailability evaluation. Int J Pharm 2019; 555: 270-279
• 181 Teiten MH, Dicato M, Diederich M. Curcumin as a regulator of epigenetic events. Mol Nutr Food Res 2013; 57: 1619-1629
• 182 Soleimani V, Sahebkar A, Hosseinzadeh H. Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review. Phytother Res 2018; 32: 985-995
• 183 Feng T, Wei Y, Lee RJ, Zhao L. Liposomal curcumin and its application in cancer. Int J Nanomedicine 2017; 12: 6027-6044

Publication History

Received: 01 August 2024

Accepted after revision: 11 November 2024

Accepted Manuscript online:
17 December 2024

Article published online:
18 March 2025