Inhibitory effect of curcumin on the proliferation of breast cancer cell lines. Breast cancer cell lines were treated with curcumin for 72 h. Cell proliferation was determined by the MTT assay, and IC50 was calculated by four-parameter non-linear regression using GraphPad Prism v.

A Dose-response curve of curcumin in various breast cancer cell lines. B IC50 of curcumin in various breast cancer cell lines. Data represent mean ± standard deviation from three independent experiments. To explore the mechanism underlying the antiproliferative action of curcumin, alterations in the cell cycle induced by curcumin were evaluated.

T47D and MCF7 cells were treated with 10 or 30 µM curcumin for 24 h, and the cell cycle was evaluated by flow cytometry. A T47D cells were treated with 10 or 30 µM curcumin for 24 h, and the cell cycle was assessed by propidium iodide PI staining using flow cytometry. B MCF7 cells were treated with 10 M or 30 µM curcumin for 24 h, and the cell cycle was assessed by PI staining using flow cytometry.

Data represent mean values from three independent experiments. Next, the effect of curcumin on cell apoptosis was investigated.

T47D and MCF7 cells were treated with 10 or 30 µM curcumin for 24 h. The results demonstrated that curcumin promoted cell apoptosis.

We calculated the early apoptosis upper right and later apoptosis lower right , and the total apoptotic ratio of T47D cells increased from 7. Similarly, in MCT7 cells, the total apoptosis rate increased from 5. In addition, curcumin at 30 µM induced some cell debris in T47D and MCF7 cells, as the increased percentage of upper left area.

These results revealed that curcumin promoted the apoptosis of breast cancer cells, and MCF7 cells appeared to be more sensitive to curcumin-induced apoptosis compared with T47D cells. Curcumin induced apoptosis in breast cancer cells. A T47D cells were treated with 10 or 30 µM curcumin for 48 h, and cell apoptosis was determined by Annexin V and propidium iodide PI staining using flow cytometry.

B MCF7 cells were treated with 10 or 30 µM curcumin for 48 h, and cell apoptosis was determined by Annexin V and PI staining using flow cytometry.

To achieve a better understanding of how curcumin inhibits the cell cycle and promotes apoptosis, the expression of key signaling molecules involved in these processes was determined by western blotting. As seen in Fig. Effects of curcumin on cell cycle, proliferation and apoptosis-related proteins.

A Curcumin inhibited the expression of CDC25 and CDC2, promoted the expression of P21, and inhibited the phosphorylation of Akt, mTOR and S6 after 12 h of treatment.

B Curcumin decreased the expression of the anti-apoptotic protein BCL2, increased the expression of the apoptotic protein BAX, and induced the cleavage of caspase 3 after 12 h of treatment.

The band intensity was analyzed by Image J software, and the expression of proteins is presented as normalized values divided by the control group. Curcumin was also found to promote apoptosis of breast cancer cells; thus, the expression of cell apoptotic proteins, such as BCL2, BAX and caspase 3, was also analyzed.

BCL2 is an anti-apoptotic protein, while BAX is a pro-apoptotic protein. Curcumin is a well-known natural compound, which has been shown to have pleotropic pharmacological properties, such as antifungal and antitumor properties 12 — In the present study, we investigated the antitumor activity of curcumin in breast cancer.

Curcumin was found to be a potent inhibitor on breast cancer cells in vitro , with an IC 50 at the micromolar level. To further investigate the molecular mechanism underlying the inhibitory effects of curcumin, T47D and MCF7 cells were selected, as they were found to be more sensitive to its actions.

The molecular mechanism underlying this action of curcumin was further explored. We found that curcumin decreased the expression of CDC25 and CDC2 and increased the expression of P The mTOR pathway, in addition to cancer, is also implicated in the pathogenesis of autoimmune 22 , 23 and infectious diseases 24 — Thus, we hypothesized that curcumin may also have therapeutic potential in autoimmune and infectious diseases, such as HIV infection.

In addition, curcumin may also promote the mitochondrial apoptotic pathway in breast cancer cells, further supporting the therapeutic value of curcumin in breast cancer. Although the preclinical data of curcumin in antitumor treatment are intriguing, several clinical studies with curcumin have yielded disappointing results.

Thus, several studies are underway aiming to develop curcumin analogues of higher potency, better bioavailability and longer half-life. For example, allylated monocarbonyl analogues and enone analogues of curcumin were found to promote mitotic arrest and apoptosis by reactive oxygen species-mediated stress 27 , Novel curcumin analogues exhibited high potency in castration-resistant prostate cancer 29 and nasopharyngeal carcinoma Interestingly, novel curcumin derivatives may exhibit high potency in triple-negative breast cancer cells 31 , 32 ; curcumin exhibited lower activity in these cancers cells in the present study, and suggested that optimization of curcumin structure may expand its therapeutic spectrum.

Thus, these results may provide a basis for further study of curcumin in the treatment of breast cancer. The authors would like to thank the Science and Technology Bureau of Shaoxing for awarding the grant.

The present study was supported by a grant from the Science and Technology Bureau of Shaoxing grant no. SH and HS were responsible for the conception and design of the study. SH, LM and LH collaborated in the development of methodology.

SH, LM and HS acquired the data. SH, LM, YX and HS wrote and revised the manuscript. DeSantis CE, Ma J, Sauer Goding A, Newman LA and Jemal A: Breast cancer statistics, , racial disparity in mortality by state.

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Curcumin 1,7-bis 4-hydroxymethoxyphenyl -1,6-heptadiene-3,5-dione , is a hydrophobic polyphenol Fig. It interacts with arsenals of molecules including inflammatory mediators, growth factors, enzymes, carrier proteins, metal ions, tumor suppressors, transcription factors, oncoproteins and cellular nucleic acids [ 17 ].

The interaction can be either indirectly or directly through covalent, non-covalent hydrophobic, and hydrogen bonding [ 18 ].

Its chemical structure with its different binding capacity is vital to its ability to interact with diverse targets. The reduced solubility and as a result lessened bioavailability is a recognized problem in the efficacy of curcumin. Solvents like dimethyl sulphoxide DMSO , ethanol and sodium hydroxide are commonly used for dissolving curcumin.

However studies showed that its solubility in water was significantly augmented with the application of heat [ 19 , 20 ]. The source and chemistry of curcumin. a Turmeric powder is obtained from the roots of plant Curcuma longa. b Curcumin is a component of turmeric. c The chemical structure of curcumin demonstrates a bis a, b-unsaturated diketone structure that displays keto enol tautomerism, with a predominant keto form in acidic and neutral solutions and a stable enol form in alkaline media.

d The chemical structure of demethoxycurcumin and bisdemethoxycurcumin. The therapeutic properties of curcumin include antioxidant, antiarthritic, antiamyloid, anti-ischemic, and anti-inflammatory effect [ 21 , 22 , 23 ].

It has been shown to have protective and therapeutic efficacy against cancers of the skin, oral cavity, lung, pancreas, and intestinal tract, and to suppress tumor angiogenesis and metastasis [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].

Ever since the recognition of potential effect of curcumin on different cancer cells, different molecular studies have clarified its underlying mechanisms of actions in tumor cells.

The multimodal targeting capacity of curcumin underlies its substantial therapeutic potential against cancer. Today we know that it exerts its anticancer effect by modulating different steps of multistep molecular carcinogenesis [ 33 , 34 , 35 , 36 ] Fig.

This review will primarily focus and highlight how curcumin affects the cancer hallmarks. Curcumin targets the different phases of carcinogenesis pathway. Curcumin affects the different phases of multistep molecular carcinogenesis. It modulates the cellular and molecular hallmarks of cancer and exerts its effects by affecting DNA mutations and epigenetic aberrations.

The growth inhibitory effect of curcumin on breast cancer has been studied on different cancer models Table 1. It impedes the growth of various cancer cells, without producing any toxicity to normal cells. Modulation of multiple cell signaling pathways that are linked with cell proliferation, cell cycle regulation, cellular senescence and apoptosis contribute in the process Fig.

Targets in the curcumin mediated inhibition of breast tumor growth. Curcumin inhibits growth of breast cancer through inhibiting cancer cell proliferation, promoting apoptosis and inducing senescence by means of targeting multiple cell signaling pathways and transcription factors.

The growth and proliferation of cell is regulated by various interactions between the different molecules of cell cycle [ 37 ]. Multiple protein kinases control the major checkpoints in cell cycle and cyclin-dependent kinases CDKs and cyclins drive the cell through the cycle [ 38 ].

The expression of cyclins and CDKs are often aberrant in cancer cells and if these can be inhibited their transcription can be blocked and cell death can be induced.

Thus currently the CDKs and cyclins are rational targets for cancer therapy [ 39 ]. Again constitutive activation of many signal transduction pathways also stimulate cancer cell growth. Besides there is crosstalk between these proliferative signaling pathways and the cell cycle regulators.

In breast cancer curcumin inhibits cell proliferation by down-regulating the transcription of nuclear factor kappa B NF-κB , cyclin D and matrix metalloproteinase-1 MMP-1 [ 40 ].

The antiproliferative effect of curcumin can also take place by means of AMPK AMP-activated protein kinase alpha-COX-2 pathway [ 45 ].

Flap endonuclease 1 FEN1 represents a potent, broadly-applicable potential target for anticancer therapeutic development [ 50 ]. It is a DNA repair-specific nuclease and over-expression of FEN1 is involved in breast cancer development [ 50 ].

Curcumin may inhibit breast cancer cell proliferation through the transcription factor Nuclear factor erythroid-derived 2 -like 2 Nrf2 mediated down-regulation of Fen1 expression [ 51 ].

Apoptosis is a highly regulated mechanism by which cells undergo cell death. Inducing apoptosis in malignant cells without damaging normal cells is an effective but challenging anticancer approach. Curcumin has strong effect on both intrinsic and extrinsic pathways of apoptosis [ 52 ]. In breast cancer curcumin mediated apoptosis can take place through both p53 dependant and independent pathways.

Curcumin induced apoptosis in breast cancer cell is dose- and time-dependent and is regulated by multiple signaling pathways [ 43 , 53 , 54 ]. With curcumin treatment tumor-free survival was prolonged and tumor multiplicity was reduced in BALB-neuT mice [ 43 ].

It induced apoptosis via a pdependent pathway where Bax is the downstream effector [ 55 , 56 ]. Curcumin alone or in combination with arabinogalactan promoted apoptosis by raising the ROS level, altering mitochondrial membrane and reducing glutathione [ 56 ].

Curcumin mediated induction of apoptosis by depletion of reduced glutathione has not been observed in breast cancer.

It also induced apoptosis in breast cancer cells through up-regulating p21 expression [ 58 ]. There was high levels of ROS generation only in breast cancer cells, which deactivated anti-apoptotic proteins like phosphorylated p53 and phosphorylated Bad and led to activation of apoptosis [ 59 ].

In combination with trichostin curcumin induces p53 independent apoptosis via c-Jun-N-terminal kinase JNK activation [ 60 ]. With berberine, curcumin induced caspase-dependent apoptosis in breast cancer cells via ERK Extracellular Signal-regulated Kinase pathways. Apoptosis is also induced in the breast cancer cells by curcumin mediated inhibition of intracellular fatty acid synthase expression [ 62 ].

Notch gene family encodes evolutionarily conserved cell surface receptor. Overexpression of these receptors has been associated in breast cancer where Notch1 can be a transcriptional target of mutant p53 [ 63 , 64 ]. Apoptosis in breast cancer cells can occur with abrogation of aberrant Notch1 signaling [ 64 ].

Treatment with curcumin resulted in downregulation of Notch1 and its downstream target, Hes1 due to the decreased activity of endogenous mutant p53 [ 65 ].

The tumor necrosis factor TNF - related-apoptosis-inducing ligand TRAIL is a potential anticancer agent, Once bound to the receptor, it leads to apoptosis by activating caspase-8 and downstream executioner caspases [ 66 ]. To normal cells TRAIL is pretty nontoxic.

But it selectively fuels apoptosis in many transformed cells. Resistance is a major hurdle to the extensive use of TRAIL-based mono-therapies.

Curcumin enhances TRAIL-induced apoptosis in breast cancer cells by regulating apoptosis-related proteins [ 67 ].

BRCA1 dysfunction is linked to triple negative breast cancer TNBC [ 68 ]. In TNBC cell lines curcumin induces double-strand breaks in DNA and increases expression as well as phosphorylation of DNA repair protein BRCA1. With cytoplasmic retention of BRCA1, DNA repair is hampered and cells undergo apoptosis [ 68 ].

Insulin like growth factors IGFs act as strong mitogens for a variety of cancer cells. The IGF-1 system has been implicated to play a critical role in breast carcinogenesis.

This system comprises IGFs IGF-1 and IGF-2 , IGF-1 receptor IGF-1R and IGF binding proteins [ 69 ]. Curcumin suppresses IGF-1R gene expression at transcriptional level, down-regulates IGF-1 axis and blunts IGFstimulated breast cancer cell growth and reverses the IGFinduced apoptosis resistance [ 70 ].

Curcumin lessens the microtubule instability of breast cancer cells, activates mitotic checkpoint, delays mitotic progression from the metaphase to anaphase and thus induces p53 dependent apoptosis [ 71 ].

Senescence is irreversible growth arrest. It prevents aged or abnormal cells from anarchic proliferation and is considered as a potent tumor-suppressing mechanism [ 72 ].

Telomere attrition and activation of tumour suppressor genes are two important mechanisms of cellular senescence. Telomere length is maintained by telomerase and progressive shortening of telomeres results in cell cycle arrest.

In majority of breast cancer types telomerase is considerably activated [ 72 ]. Studies show that in breast cancer curcumin alone or in combination with silibin can inhibit telomerase expression [ 73 ]. It induces p16 INK4A -dependent DNA damage-independent senescence without senescence associated secretory phenotype in breast cancer associated fibroblasts bCAFs [ 74 ].

For delivering oxygen and nutrients to the growing tumor, angiogenesis plays a key role. It is also critical for enabling two important malignant phenotypes: metabolic deregulation and tumor spread. As we know the degree of aggressive metastasis is an important prognostic factor for patients with breast cancer.

Studies also suggests that metastasis may be an early event in the carcinogenesis process [ 75 ]. Once breast cancer has spread, treatment options are limited. Since most deaths from breast cancer occur after the disease has metastasized, inhibiting metastasis in the early phase of carcinogenesis is a potential therapeutic strategy against this cancer.

Options to interfere with angiogenic signals by natural compounds with pleiotropic actions can be an alternative approach to develop a complementary anti-angiogenesis treatment strategy.

Through down-regulation of NF-κBp65 expression and influencing its expression regulated gene products curcumin repressed tumor growth and microvessel formation in heterotopic breast cancer mouse model and inhibited migratory activity of cancer cells [ 58 , 76 ].

While antiproliferative effects of curcumin are estrogen dependent in ER-positive human breast cancer cells, its anti-invasive effect on ER-negative cells was estrogen independent [ 49 ]. In the ER negative cancer while reducing the transcript levels of vascular endothelial growth factor VEGF and basic fibroblast growth factor, it downregulated MMP-2 and upregulated tissue inhibitor of metalloproteinase TIMP Integrin α 6 β 4 is a laminin adhesion receptor linked to cancer cell invasion and migration.

Akt and NF-κB are its known downstream effectors. Curcumin inhibits integrin function and blocks integrin-dependent breast cancer cell motility and invasion [ 79 ]. Maspin mammary serpin is a serine protease inhibitor. It can suppress tumor growth and metastasis in vivo and tumor cell motility and invasion in vitro.

It links with the p53 tumor-suppressor pathway and functions as angiogenesis inhibitor both in vitro and in vivo [ 80 ]. Curcumin has shown to upregulate maspin expression in breast cancer cells [ 81 ]. While progressive loss of expression of maspin during tumor progression makes it a noteworthy biomarker, its curcumin mediated re-expression intervention offers a promising therapeutic option for breast cancer.

Curcumin inhibits LPA-induced cancer cell invasion by attenuating this pathway [ 82 ]. Activated cancer-associated fibroblasts or myofibroblasts facilitate tumor growth. Curcumin suppressed the procarcinogenic effects of stromal fibroblast [ 74 ]. It also repressed the O -tetradecanoylphorbolacetate TPA -induced MMP-9 expression and subsequent cell invasion [ 83 ].

It inhibited metastatic development via the suppression of urokinase- type plasminogen activator through NF-κB signaling pathways [ 84 ]. The association of breast cancer with obesity is linked to adipokines like visfatin [ 85 , 86 ]. It was found that visfatin-Notch1 axis contributes to breast cancer progression [ 85 ].

Curcumin down-regulated the mRNA and protein levels of visfatin partly by NF-κB dependent mechanism [ 87 ]. When treated with curcumin there was a substantial low level of expression of pro-angiogenic factors and a decrease in micro-vessel density in animals compared with that of vehicle treated tumors [ 88 ].

Curcumin revokes osteopontin OPN and progestin induced VEGF expression [ 89 ]. OPN upregulates expression of VEGF in human breast cancer model and pledges the angiogenesis [ 90 , 91 ]. The chemokine-like extracellular matrix-associated protein OPN is pivotal in controlling breast cancer progression.

Aiming the OPN-regulated signalling pathway by curcumin to turn off the angiogenic switch could be clinically valuable emergent tactic to the treatment of the disease. With epithelial-mesenchymal transition EMT cancer cells attain molecular changes facilitating anomalous cell-cell adhesive interactions and junctions [ 92 ].

The cells morphologically become more spindle-shaped with subsequent loss of cell polarity and cell to cell adhesion [ 92 ]. This promotes cancer cell progression and spread. Once migrated to an appropriate location these cells upregulate epithelial markers through mesenchymal-epithelial transition.

Subsequently there is activation of several transcriptional repressors through various vital signaling pathways like NF-κB, Wnt and Hedgehog [ 93 , 94 ]. Therefore blocking or reversing EMT can be a promising anticancer strategy for restricting cancer spread. In breast cancer curcumin disrupts EMT and corresponding morphological changes with inhibition of cell motility and invasiveness in vitro [ 95 ].

It was also observed that curcumin decreased the expression of EMT related genes Slug, AXL and Twist1 in breast cancer cell lines [ 96 ]. Chronic inflammation aids growth and spread of cancer through either direct interactions of inflammatory cells and cancer cells or indirect effects of inflammatory cells on other resident stromal cells.

The cancer promoting effects of inflammation are release of growth factors, removal of growth suppressors, and enhanced resistance to cell death, initiation of angiogenesis, triggering of invasion and metastasis and evasion of immune destruction.

Targeting the procarcinogenic products of inflammation like free radicals, arachidonic acid metabolites, NFκB transcription factor, TNF-alpha TNF-α , CXC chemokines and AKT can be an important approach to halt cancer development and progression. Curcumin can inhibit iNOS inducible nitric oxide synthase induction, scavenge NO radicals in breast organ culture system and reduce free radical synthesis in the promotion phase of carcinogenesis [ 97 , 98 ].

It can also downregulate CXC chemokines in via the NFκB pathway [ 78 ]. Reprogramming of cellular energetic pathways in cancer cell is now a well-accepted fact which can be due to oncogene expression or inflammatory microenvironment [ 15 , 99 ]. In cancer cells there is glucose amplified uptake and glycolysis.

A substantial portion of glucose carbon from the augmented glycolytic catabolism is diverted to energize the cancer cell proliferation [ ]. It was found that the inflammatory mediator TNF-α is a direct inducer of aerobic glycolysis and inhibitor of mitochondrial biosynthesis in malignant breast epithelial cell lines.

Intriguingly this effect of TNF-α can be reversed by curcumin [ ]. CSCs are tumor initiators and propagators of tumor growth. CD44 is an important cell surface markers for bCSCs. It is a downstream target gene of STAT3-NFκB signaling pathway. The spread of cancer is mediated by cellular component that displays high CD44 activity and is associated with an elevated level of microtentacles McTNs [ , ].

McTNs aid in cell reattachment in the metastatic cascade. Alone or in combination with epigallocatechin gallate, curcumin blocked STAT3 phosphorylation, weakened the interaction between STAT3 and NFκB in the nucleus with downregulation of CD44 expression and resultant reduction in bCSC population [ ].

Curcumin inhibited the bCSC subpopulation also by extinguishing McTNs [ ]. Alone or in combination with piperine it is able to inhibit breast stem cell self-renewal through possible inhibition of Wnt signaling [ ]. Moreover this combination downregulated stearoyl-coa desaturase, the regulator of stemness in breast stem cells [ ].

This is clinically crucial as it can serve as an effective cancer preventing approach. A decreased expression of E-Cadherin, a transmembrane glycoprotein of cell adhesion, is associated with metastatic potential with poor prognosis in breast cancer.

Breast CSCs are highly migratory cells. In these cells expression of E-cadherin is suppressed thus EMT is instigated.

Hence this phytochemical can block bCSC migration and impede the EMT. The interplay between antitumor immunity and tumor-originated proinflammatory activity is thwarted in tumor microenvironment [ 15 , ]. Modulation of immune cells and the inflammatory process in order to manipulate the tumor microenvironment demonstrate attractive targets for therapeutic intervention in cancer.

Again agents that can inhibit cancer-stroma crosstalk may augment conventional tumor cell directed therapy. It is recognised that exosomes secreted from the tumor cells fuses with the T cell and NK cell to supress their cytotoxicity and thereby promotes immune tolerance.

In breast cancer curcumin can reverse this repression of NK cell cytotoxicity. In fact curcumin treatment enhances ubiquitination of exosomal proteins for degradation [ ].

While curcumin has shown to have suppressive effect on bCAFs further study is looked-for to explore the effect of curcumin on the cross talks between cancer cell and stromal cells.

Cutting-edge research should also focus on the immunomodulatory effects of this phytochemical on lymphoid cell populations, and cytokine production. Deeper understanding is needed as to whether it can be used alone or in combinations with different immunotherapies to therapeutic advantage.

Micro RNAs miRNAs are short non-coding RNA, each of which has the ability to regulate the expression of numerous genes. This feature allows them to simultaneously control multiple cellular signalling pathways.

MiRNAs have been found to be dysregulated in nearly every types of human cancer including breast cancer [ , ]. A slight change in the expression of one can generate a signaling cascade that has the potential to involve many molecular networks triggering various responses in cancer cell.

Hence, miRNAs can be either targets or effectors. Since curcumin exerts its anticancer effects by targeting multiple signalling pathways, and miRNAs regulate diverse biological processes, it is thought that miRNAs could play a role in regulating response towards this natural agent Fig.

This could lead to development of more effective treatment approaches. Whereas quite a few studies on various cancer demonstrated the anticancer effect of curcumin via modulation of miRNA, at present only few studies reveal curcumin-mediated miRNA regulation in breast cancer [ ].

Till now in breast cancer largely apoptosis, proliferation, invasion and metastasis have been found to be regulated by targeting miRNAs. In MCF-7 cells curcumin reduced Bcl-2 expression through upregulation of miRa and miR and prompted cancer cell death [ ].

Yet again when combined with emodin there was a synergism in its antiproliferative and anti-invasive effect through up-regulation of miRa [ ].

As chronic inflammation promotes bystander cell survival with genomic injury it is a critical factor in the spread and growth of cancer.

Subsequently there is down regulation of these proinflammatory cytokines. This up-regulation of miRb inhibits metastases formation in vivo in immune-deficient mice [ ].

The plastic derived universal chemical Bisphenol A BPA is an endocrine disrupter that has a cancer promoting effect in mammary epithelial cells. Fascinatingly curcumin restrained the upregulation of miR and reversed cancer promoting effect of BPA [ ].

Curcumin exemplifies a promising natural anticancer agent for breast cancer prevention and treatment. The transcription factor STAT3 is constitutively activated in a major fraction of breast cancer types especially the estrogen negative types and TNBC [ ].

Curcumin and its analogues have been found to inhibit cancer cell proliferation, promote apoptosis and suppress bCSCs by means of modulating this multifaceted transcription factor [ , , ]. Curcumin is a good candidate for NFκB and STAT3 targeting.

It may well represent a novel category of mTOR inhibitor and can also be an effective therapeutic agent in cancers with overexpression of integrin α 6 β 4.

Curcumin mediated modulation of major events in breast carcinogenesis. Curcumin exerts its anticancer effect by modulating cell proliferation and cell cycle regulation, inducing apoptosis and senescence, inhibiting cancer spread and tumor angiogenesis, impeding tumor promoting inflammation and modulating bCSCs, tumor microenvironment, cancer immunity and miRNA.

Cancers have parenchymal and stromal component. Majority of the anticancer approach is primarily targeted towards the parenchymal part.

However, CAFs comprise a major portion of the reactive tumor stroma. Hence efficient cancer therapy should take into account the presence of these stromal cells, which actively play a part in tumor growth and spread and may well be responsible for tumor recurrence.

Curcumin might constitute an efficient fibroblast-directed therapeutic approach which may improve the outcome of classic therapeutic regimens of breast cancer. To date cytotoxic chemotherapy is the main therapeutic choice for TNBCs and with recurrence these cancers have no other treatment options.

Curcumin-based treatment strategies may well improve the survival in patients with sporadic TNBCs. Last but not least, combining curcumin with chemo-based, hormone-based and targeted therapies can be a potential approach for the management of breast cancer.

In breast cancer curcumin impedes tumor growth, malignant progression and spread. Usage of curcumin as a therapeutic agent in breast cancer is perplexed by its diverse biological activity, much of which remains unexplained.

To conclude, along with the research for the enhancement of solubility and stability of curcumin, modulation of tumor microenvironment, cancer immunity, bCSCs, and cancer related miRNAs by this agent are important aspects where cutting-edge future study is looked-for.

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J Biol Chem. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. Dickson MA, Schwartz GK.

Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. Liu Q, Loo WTY, Sze SCW, Tong Y. Curcumin inhibits cell proliferation of MDA-MB and BT breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine Int J Phytother Phytopharm. Mehta K, Pantazis P, McQueen T, Aggarwal BB.

Antiproliferative effect of curcumin diferuloylmethane against human breast tumor cell lines. Anti-Cancer Drugs. Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H, et al. Masuelli L, Benvenuto M, Fantini M, Marzocchella L, Sacchetti P, Di Stefano E, et al.

Curcumin induces apoptosis in breast cancer cell lines and delays the growth of mammary tumors in neu transgenic mice. J Biol Regul Homeost Agents.

Zhou Q, Wang X, Liu X, Zhang H, Lu Y, Su S. Curcumin enhanced antiproliferative effect of mitomycin C in human breast cancer MCF-7 cells in vitro and in vivo. Acta Pharmacol Sin. Lee YK, Lee WS, Hwang JT, Kwon DY, Surh YJ, Park OJ. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha-COX-2 in cancer cells.

J Agric Food Chem. Benhaj K, Akcali KC, Ozturk M. Redundant expression of canonical Wnt ligands in human breast cancer cell lines. Mohammadi-Yeganeh S, Paryan M, Arefian E, Vasei M, Ghanbarian H, Mahdian R, et al. MicroRNA inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway.

Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Chem Biol Interact. Shao Z-M, Shen Z-Z, Liu C-H, Sartippour MR, Go VL, Heber D, et al. Curcumin exerts multiple suppressive effects on human breast carcinoma cells.

van Pel DM, Barrett IJ, Shimizu Y, Sajesh BV, Guppy BJ, Pfeifer T, et al. An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-Spectrum target for anticancer therapeutic development.

PLoS Genet. Chen B, Zhang Y, Wang Y, Rao J, Jiang X, Xu Z. Curcumin inhibits proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression. J Steroid Biochem Mol Biol. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol.

Ramachandran C, Rodriguez S, Ramachandran R, Raveendran Nair PK, Fonseca H, Khatib Z, et al. Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines.

Lv Z-D, Liu X-P, Zhao W-J, Dong Q, Li F-N, Wang H-B, et al. Curcumin induces apoptosis in breast cancer cells and inhibits tumor growth in vitro and in vivo. Int J Clin Exp Pathol. Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G. Curcumin induces apoptosis in human breast cancer cells through pdependent Bax induction.

FEBS Lett. Moghtaderi H, Sepehri H, Attari F. Combination of arabinogalactan and curcumin induces apoptosis in breast cancer cells in vitro and inhibits tumor growth via overexpression of p53 level in vivo.

Biomed Pharmacother Biomedecine Pharmacother. Ibrahim A, El-Meligy A, Lungu G, Fetaih H, Dessouki A, Stoica G, et al. Curcumin induces apoptosis in a murine mammary gland adenocarcinoma cell line through the mitochondrial pathway.

Eur J Pharmacol. Chiu T-L, Su C-C.

With so many possible agents to investigate, conclusive evidence of true benefit is hard to come by. Because of this, the American Institute for Cancer Research does not recommend the use of supplements to protect against cancer.

But if you do take a nutritional supplement or herbal product, the goal is to do no harm: Avoid supplements that may interfere with treatment, cause side effects that could hinder adequate nutrition, or cause significant discomfort or damage to your body.

The following is a list of common nutritional supplements and herbal products used for the treatment of cancer or associated side effects.

Use it to start a conversation with your health care team about what is best for you during your treatment. This means the content, strength and purity of a supplement may vary among brands and even different batches of the same brand.

To ensure the supplement you are taking contains the ingredients listed and does not contain harmful levels of contaminants, look for the U. Pharmacopeia, Consumer Lab. com or NSF international seal of approval. The bottom line is that a healthy, well-balanced diet including lots of plant-based foods-such as whole grains, fruits and vegetables-is most strongly and consistently associated with cancer reduction and lower recurrence rates.

The beneficial effects of the vitamins and minerals contained in these foods just can't be matched with an isolated nutritional supplement or herbal product. Updated Visitor Guidelines.

Living with Cancer Home Caregivers and Family Mind, Body and Side Effects Practical Matters Sharing Hope Survivorship Treatment Choices Thrive Archive. Get THRIVE and Living with Cancer content in your inbox! Help or Harm? Nutritional supplements and cancer treatment often don't mix Turmeric is likely safe for most people, but it should be avoided during chemotherapy, radiation or blood-thinning therapies.

See our Nutritional supplements Chart for information on which supplements help or hurt. Acai berry is another supplement that's likely safe for most people, but should be avoided during chemotherapy and radiation therapy because of its antioxidant properties.

Nutritional Supplement Claims Side Effects When Not To Take It Is It Safe Otherwise? ESSIAC Antioxidant, Immune enhancing, Stimulate secretion of GI motility.

Increased stool, flu-like symptoms, slight headaches, swollen glands. It should be avoided with certain chemotherapy agents and with radiation therapy. Data has shown stimulation of breast cancer cells.

There are multiple potential interactions with chemotherapy due to its effects on the liver metabolism of some of these agents. Not recommended due to lack of evidence to support claims. HYDROGEN PEROXIDE THERAPY oxygen therapy Given orally, intravenously or by colonic irrigation.

Lethal gas embolism, tear in the bowel. Alone or in conjunction with any other therapy. Not recommended due to potential harm. In some cases, this might change the effects and side effects of a medication.

Turmeric might harm the liver. Some medications can also harm the liver. Taking turmeric along with a medication that can harm the liver might increase the risk of liver damage.

Turmeric might slow blood clotting. Taking turmeric along with medications that also slow blood clotting might increase the risk of bruising and bleeding.

Turmeric might increase how much norfloxacin the body absorbs. Taking turmeric while taking norfloxacin might increase the effects and side effects of norfloxacin.

Turmeric might change how much paclitaxel stays in the body. Taking turmeric while taking paclitaxel might change the effects and side effects of paclitaxel.

Turmeric might increase how much sulfasalazine the body absorbs. Taking turmeric while taking sulfasalazine might increase the effects and side effects of sulfasalazine.

Turmeric might increase the amount of tacrolimus in the body. This can increase the side effects of tacrolimus and even damage the kidneys. Turmeric might decrease how much talinolol the body absorbs. Taking turmeric while taking talinolol might decrease the effects of talinolol.

Turmeric might decrease how much tamoxifen is in the body. Taking turmeric with tamoxifen might decrease the effects of tamoxifen. Warfarin is used to slow blood clotting.

Taking turmeric while taking warfarin might increase the effects of warfarin and increase the risk of bleeding and bruising. Are there any interactions with herbs and supplements? Information on this website is for informational use only and is not intended to replace professional medical advice, diagnosis, or treatment.

Always check with your doctor or other medical professional before making healthcare decisions including taking any medication and do not delay or disregard seeking medical advice or treatment based on any information displayed on this website.

All rights reserved. Skip to content. Turmeric Share. NatMed Pro rates effectiveness based on scientific evidence according to the following scale: Effective, Likely Effective, Possibly Effective, Possibly Ineffective, Likely Ineffective, Ineffective, and Insufficient Evidence to Rate.

Possibly Effective for … Hay fever. Taking turmeric by mouth seems to reduce hay fever symptoms such as sneezing, itching, runny nose, and congestion.

Indigestion dyspepsia. Taking turmeric may improve indigestion in some patients. Taking curcumin, a chemical found in turmeric, by mouth may work as well as another drug, called omeprazole.

Most research shows that taking curcumin, a chemical found in turmeric, by mouth reduces depression symptoms in people already using an antidepressant. High levels of cholesterol or other fats lipids in the blood hyperlipidemia.

Taking turmeric by mouth seems to lower levels of blood fats called triglycerides. But the effects of turmeric on cholesterol levels are conflicting. Also, there are many different turmeric products available.

It is not known which ones work best. Buildup of fat in the liver in people who drink little or no alcohol nonalcoholic fatty liver disease or NAFLD. Taking turmeric extract by mouth reduces markers of liver injury in people who have this condition.

It also seems to help prevent the build-up of more fat in the liver. Swelling inflammation and sores inside the mouth oral mucositis. Taking curcumin, a chemical found in turmeric, by mouth, or as a lozenge or mouthwash, seems to prevent swelling and sores in the mouth during radiation treatment for cancer.

Taking turmeric extracts, alone or together with other herbal ingredients, can reduce pain and improve function in people with knee osteoarthritis. Turmeric might work about as well as ibuprofen for reducing pain. Taking turmeric by mouth might reduce itching that is caused by various conditions.

Possibly Ineffective for … Alzheimer disease. Taking turmeric, or a chemical in turmeric called curcumin, by mouth does not seem to improve symptoms of Alzheimer disease.

Stomach ulcers. Taking turmeric by mouth does not seem to improve stomach ulcers. When taken by mouth : Turmeric is likely safe when used short-term. Turmeric products that provide up to 8 grams of curcumin daily seem to be safe when used for up to 2 months, Also, taking up to 3 grams of turmeric daily seems to be safe when used for up to 3 months.

Some people can experience mild side effects such as stomach upset, nausea, dizziness, or diarrhea. These side effects are more common at higher doses. When applied into the rectum : Turmeric is possibly safe when used as an enema.

Taking turmeric while taking losartan might increase the effects and side effects of losartan. Herbs and supplements that might damage the liver: Turmeric might harm the liver.

Taking it with other supplements that can also harm the liver might increase the risk of liver damage. Examples of supplements with this effect include garcinia, greater celandine, green tea extract, kava, and kratom. Herbs and supplements that might lower blood sugar: Turmeric might lower blood sugar.

Taking it with other supplements with similar effects might lower blood sugar too much. Examples of supplements with this effect include aloe, bitter melon, cassia cinnamon, chromium, and prickly pear cactus.

Taking turmeric while taking norfloxacin might increase the effects and side effects of norfloxacin. Turmeric might change how much paclitaxel stays in the body. Taking turmeric while taking paclitaxel might change the effects and side effects of paclitaxel. Turmeric might increase how much sulfasalazine the body absorbs.

Taking turmeric while taking sulfasalazine might increase the effects and side effects of sulfasalazine. Turmeric might increase the amount of tacrolimus in the body.

This can increase the side effects of tacrolimus and even damage the kidneys. Turmeric might decrease how much talinolol the body absorbs. Taking turmeric while taking talinolol might decrease the effects of talinolol. Turmeric might decrease how much tamoxifen is in the body.

Taking turmeric with tamoxifen might decrease the effects of tamoxifen. Warfarin is used to slow blood clotting. Taking turmeric while taking warfarin might increase the effects of warfarin and increase the risk of bleeding and bruising. Are there any interactions with herbs and supplements?

Information on this website is for informational use only and is not intended to replace professional medical advice, diagnosis, or treatment. Always check with your doctor or other medical professional before making healthcare decisions including taking any medication and do not delay or disregard seeking medical advice or treatment based on any information displayed on this website.

All rights reserved. Skip to content. Turmeric Share. NatMed Pro rates effectiveness based on scientific evidence according to the following scale: Effective, Likely Effective, Possibly Effective, Possibly Ineffective, Likely Ineffective, Ineffective, and Insufficient Evidence to Rate.

Possibly Effective for … Hay fever. Taking turmeric by mouth seems to reduce hay fever symptoms such as sneezing, itching, runny nose, and congestion.

Indigestion dyspepsia. Taking turmeric may improve indigestion in some patients. Taking curcumin, a chemical found in turmeric, by mouth may work as well as another drug, called omeprazole. Most research shows that taking curcumin, a chemical found in turmeric, by mouth reduces depression symptoms in people already using an antidepressant.

High levels of cholesterol or other fats lipids in the blood hyperlipidemia. Taking turmeric by mouth seems to lower levels of blood fats called triglycerides.

But the effects of turmeric on cholesterol levels are conflicting. Also, there are many different turmeric products available. It is not known which ones work best. Buildup of fat in the liver in people who drink little or no alcohol nonalcoholic fatty liver disease or NAFLD.

Taking turmeric extract by mouth reduces markers of liver injury in people who have this condition. It also seems to help prevent the build-up of more fat in the liver.

Swelling inflammation and sores inside the mouth oral mucositis. Taking curcumin, a chemical found in turmeric, by mouth, or as a lozenge or mouthwash, seems to prevent swelling and sores in the mouth during radiation treatment for cancer. Taking turmeric extracts, alone or together with other herbal ingredients, can reduce pain and improve function in people with knee osteoarthritis.

Turmeric might work about as well as ibuprofen for reducing pain. Taking turmeric by mouth might reduce itching that is caused by various conditions.

Possibly Ineffective for … Alzheimer disease. Taking turmeric, or a chemical in turmeric called curcumin, by mouth does not seem to improve symptoms of Alzheimer disease.

Stomach ulcers. Taking turmeric by mouth does not seem to improve stomach ulcers. When taken by mouth : Turmeric is likely safe when used short-term. Turmeric products that provide up to 8 grams of curcumin daily seem to be safe when used for up to 2 months, Also, taking up to 3 grams of turmeric daily seems to be safe when used for up to 3 months.

Some people can experience mild side effects such as stomach upset, nausea, dizziness, or diarrhea. These side effects are more common at higher doses. When applied into the rectum : Turmeric is possibly safe when used as an enema. Taking turmeric while taking losartan might increase the effects and side effects of losartan.

Herbs and supplements that might damage the liver: Turmeric might harm the liver. Taking it with other supplements that can also harm the liver might increase the risk of liver damage.

Examples of supplements with this effect include garcinia, greater celandine, green tea extract, kava, and kratom. Herbs and supplements that might lower blood sugar: Turmeric might lower blood sugar. Taking it with other supplements with similar effects might lower blood sugar too much.

Examples of supplements with this effect include aloe, bitter melon, cassia cinnamon, chromium, and prickly pear cactus. Herbs and supplements that might slow blood clotting: Turmeric might slow blood clotting and increase the risk of bleeding.

Taking it with other supplements with similar effects might increase the risk of bleeding in some people. Examples of supplements with this effect include garlic, ginger, ginkgo, nattokinase, and Panax ginseng. Iron: There is some concern that turmeric and curcumin, a chemical found in turmeric, might prevent the body from absorbing iron.

Turmeric has most often been used by adults in doses of up to 1. It is also sometimes used in mouthwashes, gels, creams, and tonics.

Speak with a healthcare provider to find out what dose might be best for a specific condition. Fascinatingly curcumin restrained the upregulation of miR and reversed cancer promoting effect of BPA [ ].

Curcumin exemplifies a promising natural anticancer agent for breast cancer prevention and treatment. The transcription factor STAT3 is constitutively activated in a major fraction of breast cancer types especially the estrogen negative types and TNBC [ ]. Curcumin and its analogues have been found to inhibit cancer cell proliferation, promote apoptosis and suppress bCSCs by means of modulating this multifaceted transcription factor [ , , ].

Curcumin is a good candidate for NFκB and STAT3 targeting. It may well represent a novel category of mTOR inhibitor and can also be an effective therapeutic agent in cancers with overexpression of integrin α 6 β 4. Curcumin mediated modulation of major events in breast carcinogenesis.

Curcumin exerts its anticancer effect by modulating cell proliferation and cell cycle regulation, inducing apoptosis and senescence, inhibiting cancer spread and tumor angiogenesis, impeding tumor promoting inflammation and modulating bCSCs, tumor microenvironment, cancer immunity and miRNA.

Cancers have parenchymal and stromal component. Majority of the anticancer approach is primarily targeted towards the parenchymal part. However, CAFs comprise a major portion of the reactive tumor stroma. Hence efficient cancer therapy should take into account the presence of these stromal cells, which actively play a part in tumor growth and spread and may well be responsible for tumor recurrence.

Curcumin might constitute an efficient fibroblast-directed therapeutic approach which may improve the outcome of classic therapeutic regimens of breast cancer. To date cytotoxic chemotherapy is the main therapeutic choice for TNBCs and with recurrence these cancers have no other treatment options.

Curcumin-based treatment strategies may well improve the survival in patients with sporadic TNBCs. Last but not least, combining curcumin with chemo-based, hormone-based and targeted therapies can be a potential approach for the management of breast cancer.

In breast cancer curcumin impedes tumor growth, malignant progression and spread. Usage of curcumin as a therapeutic agent in breast cancer is perplexed by its diverse biological activity, much of which remains unexplained. To conclude, along with the research for the enhancement of solubility and stability of curcumin, modulation of tumor microenvironment, cancer immunity, bCSCs, and cancer related miRNAs by this agent are important aspects where cutting-edge future study is looked-for.

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Biochem Pharmacol. Jin H, Qiao F, Wang Y, Xu Y, Shang Y. Oncol Rep. Kim H, Park J, Tak K-H, Bu SY, Kim E. Chemopreventive effects of curcumin on chemically induced mouse skin carcinogenesis in BK5. Insulin-like growth factor-1 transgenic mice.

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Tumour Biol J Int Soc Oncodevelopmental Biol Med. 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.

Choudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a pdependent manner. J Biol Chem. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer.

Adv Cancer Res. Dickson MA, Schwartz GK. Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. Liu Q, Loo WTY, Sze SCW, Tong Y.

Curcumin inhibits cell proliferation of MDA-MB and BT breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine Int J Phytother Phytopharm. Mehta K, Pantazis P, McQueen T, Aggarwal BB. Antiproliferative effect of curcumin diferuloylmethane against human breast tumor cell lines.

Anti-Cancer Drugs. Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H, et al. Masuelli L, Benvenuto M, Fantini M, Marzocchella L, Sacchetti P, Di Stefano E, et al. Curcumin induces apoptosis in breast cancer cell lines and delays the growth of mammary tumors in neu transgenic mice.

J Biol Regul Homeost Agents. Zhou Q, Wang X, Liu X, Zhang H, Lu Y, Su S. Curcumin enhanced antiproliferative effect of mitomycin C in human breast cancer MCF-7 cells in vitro and in vivo.

Acta Pharmacol Sin. Lee YK, Lee WS, Hwang JT, Kwon DY, Surh YJ, Park OJ. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha-COX-2 in cancer cells. J Agric Food Chem. Benhaj K, Akcali KC, Ozturk M.

Redundant expression of canonical Wnt ligands in human breast cancer cell lines. Mohammadi-Yeganeh S, Paryan M, Arefian E, Vasei M, Ghanbarian H, Mahdian R, et al. MicroRNA inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway.

Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Chem Biol Interact. Shao Z-M, Shen Z-Z, Liu C-H, Sartippour MR, Go VL, Heber D, et al. Curcumin exerts multiple suppressive effects on human breast carcinoma cells. van Pel DM, Barrett IJ, Shimizu Y, Sajesh BV, Guppy BJ, Pfeifer T, et al.

An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-Spectrum target for anticancer therapeutic development. PLoS Genet. Chen B, Zhang Y, Wang Y, Rao J, Jiang X, Xu Z. Curcumin inhibits proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression.

J Steroid Biochem Mol Biol. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. Ramachandran C, Rodriguez S, Ramachandran R, Raveendran Nair PK, Fonseca H, Khatib Z, et al. Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines.

Lv Z-D, Liu X-P, Zhao W-J, Dong Q, Li F-N, Wang H-B, et al. Curcumin induces apoptosis in breast cancer cells and inhibits tumor growth in vitro and in vivo. Int J Clin Exp Pathol. Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G. Curcumin induces apoptosis in human breast cancer cells through pdependent Bax induction.

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Curcumin induces apoptosis in a murine mammary gland adenocarcinoma cell line through the mitochondrial pathway. Eur J Pharmacol. Chiu T-L, Su C-C. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB cells.

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Download references. Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, , Kubang Kerian, Kelantan, Malaysia.

Unit of Pathology, AIMST University, Faculty of Medicine, Semeling, , Bedong, Kedah, Malaysia. Unit of Pharmacology, AIMST University, Faculty of Pharmacy, Semeling, , Bedong, Kedah, Malaysia. Unit of Microbiology, AIMST University, Faculty of Medicine, Semeling, , Bedong, Kedah, Malaysia.

You can also search for this author in PubMed Google Scholar. All four authors contributed in the preparation of this manuscript. UB made substantial contributions to conception and design; acquisition, compiling and analysis of the data; formatting and drafting the manuscript; drawing and designing the figures.

SP was involved in analysis of data; drawing the chemical structures. AKA helped in collecting and analysis of data; editing and formatting the manuscript.

NHO was responsible in revising and editing it critically for important intellectual content. All authors read and approved the final manuscript.

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