International Journal of Nutrition, Pharmacology, Neurological Diseases

REVIEW ARTICLE
Year
: 2012  |  Volume : 2  |  Issue : 2  |  Page : 92--99

Pharmacological effects of curcumin


AR Mullaicharam1, A Maheswaran2,  
1 Department of Pharmacy, Oman Medical College, Muscat, Oman
2 Research Scholar, Sastra University, Thanjavur, Tamilnadu, India

Correspondence Address:
A R Mullaicharam
Pharmacy Department, Oman Medical College, Muscat
Oman

Abstract

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Cm) is a natural product, which possesses antioxidant, anti-inflammatory, and anti-tumor activities. Curcumin (diferuloylmethane), a low molecular weight polyphenol, derived from the rhizomes of Curcuma spp., has been shown to prevent cancer in the skin, forestomach, duodenum, and colon of mice and in the tongue, colon, mammary glands, and sebaceous glands of rats. Curcumin is a member of curcuminoids isolated from Curcuma longa (turmeric). Currently, it is one of the investigational new drug substances that have great clinical potential. It was used against several ailments in India. Ever since its isolation (mid Nineteenth century), several groups from all over the world worked on its pharmacology.



How to cite this article:
Mullaicharam A R, Maheswaran A. Pharmacological effects of curcumin.Int J Nutr Pharmacol Neurol Dis 2012;2:92-99


How to cite this URL:
Mullaicharam A R, Maheswaran A. Pharmacological effects of curcumin. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Jun 15 ];2:92-99
Available from: http://www.ijnpnd.com/text.asp?2012/2/2/92/95930


Full Text

 Introduction



Curcumin is a multi-functional and pharmacologically safe natural agent. Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are polyphones and are responsible for the yellow color of turmeric. Curcumin can exist in at least two tautomeric forms, keto and enol. The enol form is more energetically stable in the solid phase and in a solution. [1]

[INLINE:1]

Chemistry

Curcumin incorporates several functional groups. The aromatic ring systems, which are polyphenols, are connected by two α, β-unsaturated carbonyl groups. The two carbonyl groups form a diketone. The diketones form stable enols or are easily deprotonated and form enolates, while the α,β-unsaturated carbonyl is a good Michael acceptor and undergoes nucleophilic addition. The structure was first identified in 1910, by Kazimierz Kostanecki, J. Miłobędzka, and Wiktor Lampe.

The biosynthetic route of curcumin has proven to be very difficult for researchers to determine. In 1973, Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involved a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involved two cinnamate units being coupled together by malonyl-CoA. Both mechanisms used cinnamic acid as their starting point, which was derived from the amino acid phenylalanine. This is noteworthy because plant biosyntheses employing cinnamic acid as a starting point are rare compared to the more common use of p-coumaric acid [Figure 1],[Figure 2],[Figure 3],[Figure 4] and [Figure 5]. [3]{Figure 1}{Figure 2}{Figure 3}{Figure 4}{Figure 5}

Anti-cancer activity of curcumin

Curcumin (diferuloylmethane) is a phytochemical that has potent antiproliferative effects against a variety of tumors in vitro. It exerts its effects via diverse biological properties, including, but not limited to, suppression of nuclear factor-nB (NF-nB) and inhibition of angiogenesis. It also enhances the antitumor effects of several classic chemotherapeutic drugs, such as doxorubicin, cis-platinum, and paclitaxel [Figure 6],[Figure 7],[Figure 8] and [Figure 9]. [4],[5],[6]{Figure 6}{Figure 7}{Figure 8}{Figure 9}

Curcumin, derived from the rhizome of Curcuma longa L, having both antioxidant and anti-inflammatory properties, inhibits chemically induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or post initiation stages. This study has been designed to investigate the chemopreventive action of curcumin when it is administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. We also studied the modulating effect of this agent on apoptosis in the tumors. At five weeks of age, groups of male F344 rats were fed a control diet containing no curcumin and an experimental AIN-76A diet with 0.2% synthetically derived curcumin (purity, 99.9%). At seven and eight weeks of age, rats intended for carcinogen treatment were given subcutaneous injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight per week. Animals destined for the promotion/progression study received the AIN-76A control diet for 14 weeks after the second AOM treatment and was then switched to diets containing 0.2 and 0.6% curcumin. Premalignant lesions in the colon would have developed by week 14, following the AOM treatment. They continued to receive their respective diets until 52 weeks after carcinogen treatment, after which were then sacrificed. The results confirmed our earlier study, in that, administration of 0.2% curcumin during both the initiation and post-initiation periods significantly inhibited colon tumor genesis. In addition, administration of 0.2 and of 0.6% of the synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon. The inhibition of adenocarcinomas of the colon was, in fact, dose-dependent. Administration of curcumin to the rats during the initiation and post-initiation stages and throughout the promotion/progression stage increased apoptosis in the colon tumors as compared to colon tumors in the groups receiving AOM and the control diet. Thus, chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment, as well as when it is given only during the promotion/progression phase (starting late in the premalignant stage) of colon carcinogenesis. [7]

On a pharmacological basis, the role of curcumin in chronic diseases: An age-old spice with modern targets.

Anticancer potential

Curcumin has been shown to exhibit therapeutic potential against a variety of different cancers including leukemia and lymphoma; gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma. The current status of curcumin's anticancer potential against various cancers is systematically analyzed and presented below under different headings.

Breast cancer

Several reports have described the anticarcinogenic activity of curcumin in a variety of breast cancer cell lines. One of our early studies established that the antiproliferative effect of curcumin in human breast cancer cell lines, including hormone-dependent, hormone-independent, and multidrug-resistant cells, was time- and dose-dependent, and correlated with curcumin's inhibition of the ornithine decarboxylase activity. [9] Several mechanisms have been proposed to account for the action of curcumin in breast cancer cells. For example, curcumin was found to inhibit the aryl hydrocarbon receptor and cytochrome P450 1A1; [9] the tyrosine kinase activity of p185neu; the expression of Ki-67, PCNA, p53 mRNAs; and COX-1 and COX-2 enzymes. Curcumin also induced p53-dependent Bax expression, inhibited the vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), [10],[11] disrupted the mitotic spindle structure and induced micro-nucleation. [12] It has been shown to inhibit telomerase activity through human telomerase reverse transcriptase, [13] downregulate the expression of matrix metalloproteinase-2 (MMP-2), upregulate the tissue inhibitor of metalloproteinase-1 (TIMP-1), [14] and block NF-kB and AP-1 activation. [15],[16],[17],[18] Studies have also shown that curcumin inhibits LOX pathways, [19] induces the degradation of cyclin E expression through a ubiquitin-dependent pathway, upregulates cyclin-dependent kinase inhibitors p21 and p27, [20] and downregulates the insulin-like growth factor-1 (IGF-1) [21] in breast cancer cell lines.

Esophageal cancer

Curcumin could be a potential candidate for use in the treatment of esophageal cancer, few studies have examined it in this disease and no in vitro evaluations of its anticancer effects in esophageal cancer cells have been reported. However, curcumin was found to inhibit the cytokine-induced activation of iNOS, JNK, VCAM, and NF-kB in human esophageal microvascular endothelial cells isolated from normal human esophageal tissues, [22] as an inflammatory molecule like NF-kB is over expressed in several tumor tissues; these results may be indirect evidence that curcumin may be effective against esophageal cancer. Two in vivo studies have been reported with curcumin in esophageal cancer. In one, dietary curcumin (500 ppm) fed during the initiation and post-initiation stages inhibited the incidence of esophageal carcinogenesis by 27 and 33%, respectively, in rats. [23] In another study, the efficacy of curcumin as a chemopreventive agent was assessed by measuring the modulation in the incidence of neoplastic change in a rat esophagus. [24]

Intestinal cancer [25]

Thus far, the efficacy of curcumin in intestinal cancer has been shown in a few animal studies. In vivo studies using mouse models have proved that curcumin modifies apoptosis resistance, leading to the inhibition of tumor formation and the prevention of adenoma development in the intestinal tract. The chemopreventive effect of curcumin for intestinal tumors in Min/+ mice was investigated. A dietary level of 0.15% curcumin decreased tumor formation in Min_/_mice by 63%. Examination of intestinal tissue from the treated animals showed that the tumor prevention by curcumin was associated with increased enterocyte apoptosis and proliferation. Curcumin also decreased the expression of the oncoprotein b-catenin in the erythrocytes of the Min/+ mouse, an observation previously associated with an anti-tumor effect.

Hepatic cancer

Curcumin significantly reduced the number of gammaglutamyl transpeptidase-positive foci, a characteristic considered to be the precursor of hepatocellular neoplasm, in rats. Curcumin also had anticarcinogenic effects mediated through the induction of glutathione-linked detoxification enzymes in rat livers. Curcumin also prevented the induction of hepatic hyperplastic nodules, body weight loss, and hypoproteinemia in carcinogen-induced as well as xenograft hepatic cancer models. Both curcumin and curcumin complexed with manganese prevented the increase of hepatic lipid peroxidation, expressed as an MDA level in mice.

Pancreatic cancer

Research over the past decade has indicated that curcumin has an anticarcinogenic effect in various pancreatic cell lines, with numerous mechanisms having been proposed, to account for this effect. In human pancreatic cancer MIA PaCa-2 cells, curcumin was found to inhibit the farnesyl protein transferase. [7] Also, NF-kB was found to be overexpressed in human pancreatic tumor tissues and cell lines; investigators suggested that this overexpression could be inhibited by curcumin because it had the ability to suppress NF-kB expression. [26],[27],[28]

Colorectal cancer

Studies using various colorectal cell lines have proven curcumin's use as a therapeutic agent as it has ability to act through numerous target molecules. For example, curcumin has been shown to disrupt Lovo cells in the S, G2/M phase and interrupt Wnt signaling and adhesion pathways causing G2/M phase arrest and apoptosis in HCT-116 cells, regardless of prostaglandin synthesis. Curcumin-induced apoptosis is a result of PARP cleavage, caspase 3, reduction in Bcl-xL level, and the increased activity of caspase-8, which encourages the Fas signaling of apoptosis. Curcumin reduces the NAT1 mRNA expression and AF-DNA adducts formation in human colon tumor cells. Curcumin has been seen to inhibit the proliferation of cells and induce apoptosis in colorectal cell lines. [9],[29] Risk factors for colon cancer consist of both hereditary and environmental factors. Dietary patterns represent controllable risk factors for the development of colon cancer. Much concentration has focused on declining the threat of colon cancer through the growing intake of dietary fiber; recently, this has incorporated understanding in the use of prebiotics and probiotics. [30]

Bladder cancer

Numerous reports indicate that curcumin has activity against bladder cancer. For example, curcumin has been shown to suppress the proliferation of bladder cancer cells in the culture either through the suppression of NF-kB [31],[32] or through the downregulation of cyclin A and upregulation of p21. [33] Certain synthetic analogs of curcumin have been shown to exhibit activity against bladder cancer cell lines. [34],[35]

Kidney cancer

In human kidney cancer cells, curcumin upregulates apoptotic events such as cell shrinkage, chromatin condensation, and DNA fragmentation [36] and inhibits FPTase. [37] Curcumin serves as a COX-1and COX-2 inhibitor; [38] inhibits microsomal lipid peroxidation and DNA damage; [39] deactivates the Akt pathway; downregulates Bcl-2, Bcl-xL, and IAP proteins; [40] and increases (Tumor Necrosis Factor-Alpha-Related Apoptosis-Inducing Ligand) TRAIL-induced apoptosis by augmenting DR5 expression at the mRNA and protein levels, by producing reactive oxygen species (ROS). [41] In HKC cells, curcumin reduces tumor growth and side effects when activated via the hydrolysis of prodrugs. [34] An in vivo study demonstrated that dietary curcumin treatment reduced risk for kidney cancer metastasis in rats. [42]

Prostate cancer

Curcumin has shown activity against various prostate cancer cells, such as LNCaP, DU145, C4-2B, and PC3. Curcumin can induce programmed cell death in androgen-dependent and androgen-independent prostate cancer cells. It can inhibit capillary tube formation and cell migration and exert significant effects on the actin cytoskeletons in prostate cancer cells. [9],[43],[44],[45]

Cervical cancer

Curcumin modulates the in vitro expression and function of P-gp in multidrug-resistant human KB-V1 cells [9],[46] and sensitizes cisplatin-resistant SiHa cells to cisplatin-induced apoptosis, [47] indicating its ability to reverse MDR in cervical cancer cells. The effect of curcumin in HPV-associated cells was found to involve the downregulation of viral oncogenes, NF-jB and AP-1. [9],[48] Similarly, a major metabolite of curcumin called THC increased the sensitivity of vinblastine, mitoxantrone, and etoposide in a drug-resistant human cervical carcinoma cell line. [49] In a phase I clinical trial, a daily dose, 0.5 - 12 g, of curcumin, taken orally for three months resulted in the histological improvement of precancerous lesions in one out of four patients with uterine cervical intraepithelial neoplasms.

Ovarian cancer

In these ovarian tumors, curcumin alone and with docetaxel decreased both proliferation and micro-vessel density and increased tumor cell apoptosis. In mice with multidrug-resistant ovarian tumors, treatment with curcumin alone and combined with docetaxel resulted in a significant 47 and 58% reductions in tumor growth, respectively. [50]

Pulmonary cancer

Curcumin exhibits anticancer effects in various lung cancer cells through a variety of molecular targets. At the cellular level, curcumin derivatives inhibit FPTase in A549 cells. Curcumin inhibits AP-1 transcription and mediastinal lymph node metastasis in Lewis lung carcinoma cells and ornithine decarboxylase activity in rat tracheal epithelial cells. [51],[52]

Bone cancer

In an in vivo study on rats, dietary curcumin with cisplatin modulated tumor marker indices of fibrosarcoma toward normal controls. Treatment with radiotherapy and curcumin resulted in enhanced tumor cell-killing and reduced radio resistance in mice bearing fibrosarcoma, as indicated by the significant inhibition of radiation-induced ERK and NF-kB expression. [53]

Brain tumor

Malignant gliomas are a debilitating class of brain tumors that are resistant to radiation and hemotherapeutic drugs. The therapeutic efficacy of curcumin in various human malignant glioblastoma cells has been established, [54] and curcumin has been found to inhibit the NF-kB signaling pathways in these cell lines. [55],[56],[57] The neuroleptic malignant syndrome is a rare and potentially serious syndrome associated with the use of many antipsychotics, antiparkinsonian drugs, antidepressants, and so on. [58]

Control of cancer symptoms by curcumin

Patients with cancer suffer from various treatment-related symptoms, including neuropathic pain, depression, fatigue, decreased appetite, and sleep disturbance. Many of these symptoms may cause treatment delays and prevent the delivery of full-dose therapy in the scheduled time. In the course of targeting cancer, most chemotherapeutic agents activate NF-kB and induce TNF release. Consequentially, many of the symptoms related to cytokine deregulation are affected by both the disease and the treatment. For example, chemotherapy commonly causes neuropathic pain, depression, fatigue, decreased appetite, and sleep disturbance, all of which have been linked to proinflammatory pathways that include NF-kB and TNF, as well as other key factors, such as IL-1 and IL- 6. [59],[60] Animal models of.'sickness behavior' support this thesis, [61],[62] in that, fluctuations in inflammatory cytokines, primarily IL-1, IL-6, and TNF-a, are related to fluctuations in components of sickness in animals (e.g., anorexia, disturbed sleep, hyperalgesia, and disrupted learning). The administration of these cytokines can produce sickness in behavior, which in turn, can be eliminated by antibodies to these cytokines. The fact of curcumin can suppress the activation of NF-kB and NF-kB-regulated TNF, IL- 1, and IL-6 expression, indicates that it may have a potential effect against these symptoms.

Anti-inflammatory activity of curcumin

Extensive scientific research on curcumin, a natural compound present in the rhizomes of Plant Curcuma Longa Linn., demonstrated its anti-inflammatory action. Curcumin was found to inhibit arachidonic acid metabolism, cyclooxygenase, lipoxygenase, cytokines (Interleukins and tumor necrosis factor), Nuclear factor-κB, and release of steroidal hormones. Curcumin was reported to stabilize the lysosomal membrane and cause uncoupling of oxidative phosphorylation besides having a strong oxygen radical scavenging activity, which was responsible for its anti-inflammatory property. In various animal studies, a dose range of 100 - 200 mg/kg body weight exhibited good anti-inflammatory activity and seemed to have a negligible adverse effect on human systems. Oral LD50 in mice was found to be more than 2.0 g/kg body weight.

Curcumin and anti-inflammatory activity

Arora et al. reported anti-inflammatory activity in different fractions of the petroleum ether extract of Curcuma longa. [64] The total petroleum ether extract of the rhizome of turmeric and two of its fractions A and B were evaluated for their anti-inflammatory activity in albino rats (180 - 200 g) and compared with that of hydrocortisone acetate and phenylbutazone. It was found that the anti-inflammatory activity of the total petroleum ether extract was less than the individual fractions A and B. The fractions were almost as active as hydrocortisone acetate in the inflammation induced by the cotton pellet method. Curcumin isolated from the alcoholic extract of turmeric has been shown to be a useful anti-inflammatory agent. In subacute toxicity experiments, no significant toxic side effects were observed in rats when the extract was administered for four weeks at the dose level of 1 - 2 g/kg. Oral LD50 was found to be 12.2 g/ kg. [64] In recent times, the anti-inflammatory activity of curcumin has been demonstrated in acute and chronic models of inflammation in rats and mice. [65],[66] In rats with Freud's adjuvant-induced arthritis, administration of curcumin significantly reduced the inflammatory swelling compared to the control. [66] Oral doses, up to 160 mg/ kg of curcumin, failed to prevent phenyl quinone-induced inflammation in mice. In instances of acute inflammation, oral administration of curcumin was found to be as effective as cortisone or phenylbutazone, whereas, in chronic inflammation it was only half as effective. [67] Curcumin may also be applied topically to animal skin to counteract inflammation and irritation associated with inflammatory skin conditions and allergies. [67] Curcumin is a more potent antioxidant than Vitamin E. [68]

 Conclusions



As detailed in this review, curcumin can modulate multiple cellular signaling pathways and interact with numerous molecular targets. Thus, it may have the potential to act against a large number of cancers. In vitro, in vivo, and human clinical studies have all established curcumin's promise and revealed its therapeutic value. More extensive, randomized clinical trials are now needed. The safety, low cost, and already proven efficacy of this 'age old' natural medicine makes it a promising agent for the treatment of an 'old-age' disease like cancer. [25]

All of the above-mentioned reviews clearly indicate that curcumin can be used for the treatment of inflammatory diseases, different types of infections, and for many chronic diseases.

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