Molecular Targets Of Curcumin Research Articles

A network pharmacology approach to identify the mechanisms and molecular targets of curcumin against Alzheimer disease.

Background:Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumin, a major ingredient of traditional Chinese medicine, Curcuma Longa, has various pharmacological activities. Therefore, exploring clinical drugs based on the inhibition of AD pathological features is imperative.Methods:First, we utilized the HERB database and Swisstarget Prediction database to get the related targets of curcumin and intersected with the AD targets. The intersection targets were used to construct the protein-protein interaction network and performed gene ontology and kyoto encyclopedia of genes and genomes analyses. Further, we obtained targets of curcumin against AD-related tau and aβ pathology via the AlzData database. These targets were applied to perform GEO and receiver operating characteristic analyses. Finally, the reliability of the core targets was evaluated using molecular docking technology.Results:We identified 49 targets of curcumin against AD, and kyoto encyclopedia of genes and genomes pathway enrichment analysis demonstrated that the Alzheimer disease pathway (has05010) was significantly enriched. Even more, we obtained 16 targets of curcumin-related Aβ and tau pathology. Among these targets, 8 targets involved the Alzheimer disease pathway and the biological process analyses showed that positive regulation of cytokine production (GO:0001819) was significantly enriched. Bioinformatic analyses indicated that HMOX1, CSF1R, NFKB1, GSK3B, BACE1, AR, or PTGS1 expression was significantly different compared to the control group in the AD patients. Finally, molecular docking studies suggested these genes have a good binding force with curcumin.Conclusions:In this study, we identified curcumin exerted the effect of treating AD by regulating multitargets and multichannels through the method of network pharmacology.

Obstacles against the Marketing of Curcumin as a Drug.

Among the extensive public and scientific interest in the use of phytochemicals to prevent or treat human diseases in recent years, natural compounds have been highly investigated to elucidate their therapeutic effect on chronic human diseases including cancer, cardiovascular disease, and neurodegenerative disease. Curcumin, an active principle of the perennial herb Curcuma longa, has attracted an increasing research interest over the last half-century due to its diversity of molecular targets, including transcription factors, enzymes, protein kinases, growth factors, inflammatory cytokines, receptors, and it’s interesting pharmacological activities. Despite that, the clinical effectiveness of the native curcumin is weak, owing to its low bioavailability and rapid metabolism. Preclinical data obtained from animal models and phase I clinical studies done in human volunteers confirmed a small amount of intestinal absorption, hepatic first pass effect, and some degree of intestinal metabolism, might explain its poor systemic availability when it is given via the oral route. During the last decade, researchers have attempted with new pharmaceutical methods such as nanoparticles, liposomes, micelles, solid dispersions, emulsions, and microspheres to improve the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with a varying range of enhanced bioavailability. This manuscript critically reviews the available scientific evidence on the basic and clinical effects and molecular targets of curcumin. We also discuss its pharmacokinetic and problems for marketing curcumin as a drug.

Abstract C014: Development of an injectable water-soluble anticancer drug CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation

Abstract Recent well-designed preclinical studies have demonstrated that KRAS mutations can activate the canonical NF-κB signaling pathway, which is a pivotal role in tumor progression. Therefore, inhibition of this KRAS-NF-κB axis would be a promising target to develop a new molecular targeted anticancer agent. Curcumin, a naturally occurring polyphenol derived from the plant Curcuma longa, has been shown to block NF-κB signaling pathway via at least two mechanisms; inhibition of IkB phosphorylation and inhibition of ubiquitin-dependent degradation of IκB. Recently dual-specificity tyrosine-regulated kinase (DYRK2), a positive regulator of the 26S proteasome, has been reported as a direct molecular target of curcumin, which is consisted with the inhibition of NF-κB signaling pathway by curcumin. Several preclinical studies have clearly demonstrated that curcumin exhibits anticancer effects in colorectal cancer model through NF-κB inhibition. However, since curcumin is highly lipophilic and orally administrated curcumin has very low bioavailability, its clinical application in cancer patients has been hampered. Very recently we developed a synthetic water-soluble prodrug CMG, curcumin mono-β-D-glucuronide, to overcome these problems. In this study, we investigated the anticancer effect of CMG on oxaliplatin (L-OHP) -resistant colorectal cancer cells HCT116 with KRAS mutation and p53 deletion (KRAS+p53- cells). Curcumin, the active substance released from CMG in vivo, showed similar effects regardless of KRAS/p53 mutation status in vitro. In xenograft models using KRAS+p53- HCT116 cells, intraperitoneal administration of CMG significantly superior antitumor effects compared to L-OHP monotherapy. Notably, no adverse events were noted in the CMG group, whereas bodyweight loss, severe myelosuppression, and liver damage were observed in the L-OHP group. Combination of CMG and L-OHP showed additive antitumor effects with moderate suppression of liver damage by L-OHP. These results indicate that CMG could be a novel anticancer drug with minimal toxicities for colon cancer patients with KRAS and p53 mutations. Citation Format: Hideaki Kakeya, Atsuhiro Kishimoto, Hitomi Umeta, Atsushi Imaizumi, Masashi Kanai. Development of an injectable water-soluble anticancer drug CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C014. doi:10.1158/1535-7163.TARG-19-C014

Molecular targets of curcumin in breast cancer (Review).

Curcumin (diferuloylmethane), an orange‑yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of Curcumalonga. For centuries, curcumin has been used in medicinal preparations and as a food colorant. In recent years, extensive invitro and invivo studies have suggested that curcumin possesses activity against cancer, viral infection, arthritis, amyloid aggregation, oxidation and inflammation. Curcumin exerts anticancer effects primarily by activating apoptotic pathways in cancer cells and inhibiting pro‑cancer processes, including inflammation, angiogenesis and metastasis. Curcumin targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, Ras, phosphatidylinositol‑3‑kinase, protein kinase B, Wnt‑β catenin and mammalian target of rapamycin. Clinical studies have demonstrated that curcumin alone or combined with other drugs exhibits promising anticancer activity in patients with breast cancer without adverse effects. In the present review, the chemistry and bioavailability of curcumin and its molecular targets in breast cancer are discussed. Future research directions are discussed to further understand this promising natural product.

Curcumin ameliorates PRMT5-MEP50 arginine methyltransferase expression by decreasing the Sp1 and NF-YA transcription factors in the A549 and MCF-7 cells.

The protein arginine methyltransferase 5 (PRMT5) and its catalytic partner methylosome protein MEP50 (WDR77) catalyse the mono- and symmetric di-methylation of selective arginines in various histones and non-histone target proteins. It has emerged as a crucial epigenetic regulator in cell proliferation and differentiation; which also reported to be overexpressed in many forms of cancers in humans. In this study, we aimed to assess the modulations in the expression of this enzyme upon exposure to the well-studied natural compound from the spice turmeric, curcumin. We exposed the lung and breast cancer cell lines(A549 and MCF-7) to curcumin (2 and 20μM) and observed a highly significant inhibitory effect on the expression of both PRMT5 and MEP50. The level of symmetrical dimethylarginine (SDMA) in multiple proteins, and more specifically, the H4R3me2s mark (which predominates in GC-rich motifs in nucleosomal DNA) was also diminished significantly. We also found that curcumin significantly reduced the level and enrichment of the transcription factors Sp1 and NF-YA which shares their binding sites within the GC-rich region of the PRMT5 proximal promoter. Furthermore, the involvement of both PKC-p38-ERK-cFos and AKT-mTOR signalling was observed in reducing the Sp1 and NF-YA expression by curcumin. Therefore, we propose curcumin decreased the expression of PRMT5 in these cells by affecting at least these two transcription factors. Altogether, we report a new molecular target of curcumin and further elucidation of this proposed mechanism through which curcumin affects the PRMT5-MEP50 methyltransferase expression might be explored for its therapeutic application.

Multifaceted Role of a Marvel Golden Molecule, Curcumin: a Review

Curcumin is chemically known as diferuloylmethane, which is an important nutraceutical obtained from the yellow spice Curcuma longa. It has been used traditionally as a folklore medicine in countries like India, China and Thailand for nearly 2000 years without any prior knowledge of the mechanism of action. Cell-based studies and clinical trials that have been reported so far have provided evidence that curcumin could be effectively used as antimicrobial, anticancer, antidiabetic, antiinflammatory, antimalarial and antioxidant. There are more than 9400 articles published on this “magical molecule” till date. Furthermore, nearly 100 clinical trials have been done using curcumin, which demonstrated safety, efficacy and prophylactic activity of curcumin. On the molecular level, curcumin has shown to modulate several crucial and significantly interlinked pathways in rendering an optimistic outcome against life-threatening diseases like cancer, diabetes, lupus nephritis, and other autoimmune and neurodegenerative diseases. In this communication, the chemical structure, biological properties and possible molecular targets of curcumin have been reviewed along with some recent developments in drug delivery systems of curcumin.

Molecular Targets of Curcumin and Future Therapeutic Role in Leukemia

Leukemia is a most prevalent type of cancer around the globe. Due to major side effects of Chemotherapy and radiotherapy, scientists worked to explore the alternative source to treat leukemia. An alternative source for the treatment of leukemia existed in the form of curcumin, a natural phenolic compound extracted from curcuma longa plant. It exhibited anticancer properties reducing the tumor load via apoptosis and cell cycle arrested in various cancer cell lines and controlled tumor proliferation by blocking tumor inducing gene such as FLT3, Akt gene, ROS and NF-κB inhibition. At molecular level, curcumin plays a key therapeutic role in protection of normal cells by up regulation of NRF-2 that induces production of cellular antioxidants. It regulates various signaling pathways including NF-KB, JAK/STAT, PI3K/AKT and JNK pathways, thereby affecting cancer initiation, progression, and metastasis. This review described the potential of curcumin for treatment of leukemia; it affects different signaling cascades and their regulation. This study provides a preclinical foundation for future usage of curcumin in the treatment of cancer.

Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum.

ABSTRACTNatural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment, including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum. We show that curcumin exerts acute effects on cell behaviour, reduces cell growth and slows multicellular development. We employed a range of structurally related compounds to show the distinct role of different structural groups in curcumin's effects on cell behaviour, growth and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known antioxidant activity of curcumin. Molecular mechanisms underlying the effect of curcumin and one synthetic analogue (EF24) were then investigated to identify a curcumin-resistant mutant lacking the protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the presenilin 1 orthologue (PsenB). Using in silico docking analysis, we then showed that curcumin might function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of curcumin and related compounds.

Therapeutic actions of curcumin in bone disorders.

Curcumin is the active component of turmeric extract derived from the Curcuma longa plant. In the last decade, curcumin has raised a considerable interest in medicine owing to its negligible toxicity and multiple therapeutic actions including anti-cancer, anti-inflammatory and anti-microbial activities. Among the various molecular targets of curcumin, some are involved in bone remodeling, which strongly suggests that curcumin can affect the skeletal system. The review sheds light on the current and potential applications of curcumin to treat bone disorders characterized by an excessive resorption activity. Within the scope of this review, the novel formulations of curcumin to overcome its physico-chemical and pharmacokinetic constraints are also discussed.

Molecular Targets of Curcumin: A Potential Magic Bullet for Health

Molecular Targets of Curcumin: A Potential Magic Bullet for Health

Anaphase-promoting complex/cyclosome protein Cdc27 is a target for curcumin-induced cell cycle arrest and apoptosis

BackgroundCurcumin (diferuloylmethane), the yellow pigment in the Asian spice turmeric, is a hydrophobic polyphenol from the rhizome of Curcuma longa. Because of its chemopreventive and chemotherapeutic potential with no discernable side effects, it has become one of the major natural agents being developed for cancer therapy. Accumulating evidence suggests that curcumin induces cell death through activation of apoptotic pathways and inhibition of cell growth and proliferation. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell cycle control mechanism to delay the onset of anaphase during mitosis. One of the key regulators of the SAC is the anaphase promoting complex/cyclosome (APC/C) which ubiquitinates cyclin B and securin and targets them for proteolysis. Because APC/C not only ensures cell cycle arrest upon spindle disruption but also promotes cell death in response to prolonged mitotic arrest, it has become an attractive drug target in cancer therapy.MethodsCell cycle profiles were determined in control and curcumin-treated medulloblastoma and various other cancer cell lines. Pull-down assays were used to confirm curcumin binding. APC/C activity was determined using an in vitro APC activity assay.ResultsWe identified Cdc27/APC3, a component of the APC/C, as a novel molecular target of curcumin and showed that curcumin binds to and crosslinks Cdc27 to affect APC/C function. We further provide evidence that curcumin preferably induces apoptosis in cells expressing phosphorylated Cdc27 usually found in highly proliferating cells.ConclusionsWe report that curcumin directly targets the SAC to induce apoptosis preferably in cells with high levels of phosphorylated Cdc27. Our studies provide a possible molecular mechanism why curcumin induces apoptosis preferentially in cancer cells and suggest that phosphorylation of Cdc27 could be used as a biomarker to predict the therapeutic response of cancer cells to curcumin.

Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1

Prostaglandin E(2) (PGE(2)) plays a crucial role in the apparent link between tumor growth and chronic inflammation. Cyclooxygenase (COX)-2 and microsomal PGE(2) synthase-1, which are overexpressed in many cancers, are functionally coupled and thus produce massive PGE(2) in various tumors. Curcumin, a polyphenolic beta-diketone from tumeric with anti-carcinogenic and anti-inflammatory activities, was shown to suppress PGE(2) formation and to block the expression of COX-2 and of microsomal PGE(2) synthase-1. Here, we identified microsomal PGE(2) synthase-1 as a molecular target of curcumin and we show that inhibition of microsomal PGE(2) synthase-1 activity is the predominant mechanism of curcumin to suppress PGE(2) biosynthesis. Curcumin reversibly inhibited the conversion of PGH(2) to PGE(2) by microsomal PGE(2) synthase-1 in microsomes of interleukin-1beta-stimulated A549 lung carcinoma cells with an IC(50) of 0.2 to 0.3 micromol/L. Closely related polyphenols (e.g., resveratrol, coniferyl alcohol, eugenol, rosmarinic acid) failed in this respect, and isolated ovine COX-1 and human recombinant COX-2 were not inhibited by curcumin up to 30 micromol/L. In lipopolysaccharide-stimulated human whole blood, curcumin inhibited COX-2-derived PGE(2) formation from endogenous or from exogenous arachidonic acid, whereas the concomitant formation of COX-2-mediated 6-keto PGF(1)alpha and COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid was suppressed only at significant higher concentrations. Based on the key function of PGE(2) in inflammation and carcinogenesis, inhibition of microsomal PGE(2) synthase-1 by curcumin provides a molecular basis for its anticarcinogenic and anti-inflammatory activities.

Inhibition of homodimerization of Toll-like receptor 4 by curcumin

Toll-like receptors play a key role in sensing microbial components and inducing innate immune responses. Ligand-induced dimerization of TLR4 is required for the activation of downstream signaling pathways. Thus, the receptor dimerization may be one of the first lines of regulation in activating TLR-mediated signaling pathways and induction of subsequent immune responses. LPS induces the activation of NF-κB and IRF3 through MyD88- or TRIF-dependent pathways. Curcumin, a polyphenol found in the plant Curcuma longa, has been shown to suppress the activation of NF-κB induced by various pro-inflammatory stimuli by inhibiting IKKβ kinase activity in MyD88-dependent pathway. Curcumin also inhibited LPS-induced IRF3 activation. These results imply that curcumin inhibits both MyD88- and TRIF-dependent pathways in LPS-induced TLR4 signaling. However, in TRIF-dependent pathway, curcumin did not inhibit IRF3 activation induced by overexpression of TRIF in 293T cells. These results suggest that TLR4 receptor complex is the molecular target of curcumin in addition to IKKβ. Here, we report biochemical evidence that phytochemicals (curcumin and sesquiterpene lactone) inhibit both ligand-induced and ligand-independent dimerization of TLR4. Furthermore, these results demonstrate that small molecules with non-microbial origin can directly inhibit TLRs-mediated signaling pathways at the receptor level. These results imply that the activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain dietary phytochemicals we consume daily.

Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin

The antitumor effect of curcumin (diferuloylmethane) is well established. However, there have been no unbiased studies to identify novel molecular targets of this compound. We therefore undertook a gene expression profiling study to identify novel targets of curcumin. A cDNA array comprised of 12,625 probes was used to compare total RNA extracted from curcumin-treated and untreated MDA-1986 cells for differential gene expression. We identified 202 up-regulated mRNAs and 505 transcripts decreased > or =2-fold. The proapoptotic activating transcription factor 3 (ATF3) was induced >4-fold. Two negative regulators of growth control [antagonizer of myc transcriptional activity (Mad) and p27kip1] were induced 68- and 3-fold, respectively. Additionally, two dual-activity phosphatases (CL 100 and MKP-5), which inactivate the c-jun-NH2-kinases, showed augmented expression, coinciding with reduced expression of the upstream activators of c-jun-NH2-kinase (MEKK and MKK4). Of the repressed genes, the expression of Frizzled-1 (Wnt receptor) was most strongly attenuated (8-fold). Additionally, two genes implicated in growth control (K-sam, encoding the keratinocyte growth factor receptor, and HER3) as well as the E2F-5 transcription factor, which regulates genes controlling cell proliferation, also showed down-regulated expression. Considering its role in apoptosis, we determined the contribution of ATF3 to the antitumor effect of curcumin. Curcumin-treated MDA-1986 cells showed a rapid, dose-dependent increase in ATF3/mRNA protein. Moreover, expression of an exogenous ATF3 cDNA synergized with curcumin in inducing apoptosis. Thus, we have identified several putative, novel molecular targets of curcumin and showed that one, (ATF3) contributes to the proapoptotic effects of this compound.

AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells

AMP-activated protein kinase (AMPK), an evolutionarily conserved serine/threonine protein kinase, serves as an energy sensor in all eukaryotic cells. Recent findings suggest that AMPK activation strongly suppresses cell proliferation and induces cell apoptosis in a variety of cancer cells. Our study demonstrated that chemopreventive agent curcumin strongly activates AMPK in a p38-dependent manner in CaOV3 ovarian cancer cells. Pretreatment of cells with compound C (AMPK inhibitor) and SB203580 (p38 inhibitor) attenuates curcumin-induced cell death. We also observed that curcumin induces p53 phosphorylation (Ser 15) and both compound C and SB203580 pretreatment inhibit p53 phosphorylation. Collectively, our data suggest that AMPK is a new molecular target of curcumin and AMPK activation partially contributes to the cytotoxic effect of curcumin in ovarian cancer cells.