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`Author Manuscript
`Clin Exp Pharmacol Physiol. Author manuscript; available in PMC 2013 March 01.
`Published in final edited form as:
`Clin Exp Pharmacol Physiol. 2012 March ; 39(3): 283–299. doi:10.1111/j.1440-1681.2011.05648.x.
`
`Discovery of Curcumin, a Component of the Golden Spice, and
`Its Miraculous Biological Activities
`
`Subash C Gupta, Sridevi Patchva, Wonil Koh, and Bharat B Aggarwal
`Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of
`Texas MD Anderson Cancer Center, Houston, Texas, USA
`
`SUMMARY
`1. Curcumin is the active ingredient of the dietary spice turmeric and has been consumed for
`medicinal purposes for thousands of years. Modern science has shown that curcumin modulates
`various signaling molecules, including inflammatory molecules, transcription factors, enzymes,
`protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins,
`adhesion molecules, growth factors, receptors, cell-cycle regulatory proteins, chemokines, DNA,
`RNA, and metal ions.
`
`2. Because of this polyphenol's potential to modulate multiple signaling molecules, it has been
`reported to possess pleiotropic activities. First shown to have anti-bacterial activity in 1949,
`curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic,
`chemopreventive, chemotherapeutic, anti-proliferative, wound healing, anti-nociceptive, anti-
`parasitic, and anti-malarial properties as well. Animal studies have suggested that curcumin may
`be active against a wide range of human diseases, including diabetes, obesity, neurologic and
`psychiatric disorders, and cancer, as well as chronic illnesses affecting the eyes, lungs, liver,
`kidneys, and gastrointestinal and cardiovascular systems.
`
`3. Although many clinical trials evaluating curcumin's safety and efficacy against human ailments
`have already been completed, others are still ongoing. Moreover, curcumin is used as a
`supplement in several countries, including India, Japan, the United States, Thailand, China, Korea,
`Turkey, South Africa, Nepal, and Pakistan. Although inexpensive, apparently well tolerated, and
`potentially active, curcumin has yet not been approved for treatment of any human disease.
`
`4. In this article, we discuss the discovery and key biological activities of curcumin, with a
`particular emphasis on its activities at the molecular, cellular, animal, and human levels.
`
`DISCOVERY OF CURCUMIN
`The discovery of curcumin dates to around two centuries ago when Vogel and Pelletier
`reported the isolation of “yellow coloring-matter” from the rhizomes of Curcuma longa
`(turmeric) and named it curcumin (1). Later, this substance was found to be a mixture of
`resin and turmeric oil. In 1842, Vogel Jr. obtained a pure preparation of curcumin but did
`not report its formula (2). In the decades that followed, several chemists reported possible
`structures of curcumin (3–5). However, it was not until 1910 that Milobedzka and Lampe
`identified the chemical structure of curcumin as diferuloylmethane, or 1,6-heptadiene-3,5-
`dione-1,7-bis (4-hydroxy-3-methoxyphenyl)-(1E, 6E) (6). Further work by the same group
`in 1913 resulted in the synthesis of the compound (7). Subsequently, Srinivasan separated
`and quantified the components of curcumin by chromatography (8) (Fig 1A and 1B).
`
`Correspondence: Bharat B Aggarwal, PhD, Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 1950, The
`University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
`aggarwal@mdanderson.org; Phone: 713-794-1817; Fax: 713-745-6339.
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`SAB1005
`U.S. Pat. No. 10,945,970
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`Although turmeric, the major source of curcumin, has been consumed as a dietary spice and
`a cure for human ailments for thousands of years in Asian countries, the biological
`characteristics of curcumin were not scientifically identified until the mid-twentieth century.
`In a paper published in Nature in 1949, Schraufstatter and colleagues reported that curcumin
`is a biologically active compound that has anti-bacterial properties (9). The authors found
`that curcumin was active against strains of Staphylococcus aureus, Salmonella paratyphi,
`Trichophyton gypseum, and Mycobacterium tuberculosis (Fig 1C). Despite those findings,
`only five papers were published on curcumin during the next two decades. In the 1970s,
`curcumin became the subject of scientific investigation, and three independent groups
`discovered diverse characteristics of curcumin, including cholesterol-lowering (10), anti-
`diabetic (11), anti-inflammatory (12), and anti-oxidant (13) activities. Later, in the 1980s,
`Kuttan and colleagues demonstrated the anti-cancer activity of curcumin in both in vitro and
`in vivo models (14). In 1995, our group was the first to demonstrate that curcumin exhibits
`anti-inflammatory activity by suppressing the pro-inflammatory transcription factor nuclear
`factor (NF)-κB; we also delineated the molecular mechanism of the inhibition (15).
`
`The interest in curcumin research has increased dramatically over the years (Fig 1D). As of
`June 2011, more than 4000 articles on curcumin were listed in the National Institutes of
`Health PubMed database (www.ncbi.nlm.nih.gov/sites/entrez). We now know that curcumin
`can modulate multiple signaling pathways in either a direct or indirect manner. This
`polyphenol has been shown to possess activities in animal models of many human diseases.
`In human clinical trials, curcumin has been found to be safe and efficacious, and the U.S.
`Food and Drug Administration has approved curcumin as a “generally regarded as safe”
`compound.
`
`Although curcumin has shown therapeutic efficacy against many human ailments, one of the
`major problems with curcumin is its poor bioavailability (16), which appears to be primarily
`due to poor absorption, rapid metabolism, and rapid systemic elimination. Therefore, efforts
`have been made to improve curcumin's bioavailability by improving these features.
`Adjuvants that can block the metabolic pathway of curcumin have been most extensively
`used to increase the bioavailability of this polyphenol. For instance, in humans receiving a
`dose of 2 g curcumin alone, serum levels have been either undetectable or very low, but
`concomitant administration of piperine was associated with an increase of 2000% in the
`bioavailability of curcumin (17). Furthermore, the effect of piperine in enhancing curcumin's
`bioavailability has been shown to be much greater in humans than in rats (16). Other
`promising approaches to increase the bioavailability of curcumin include use of
`nanoparticles (18), liposomes (19), micelles (20), phospholipid complexes (21), and
`structural analogues (22, 23).
`
`Curcumin is now regarded as a “new drug” with great potential and is being used as a
`supplement in several countries. For example, in India, turmeric containing curcumin has
`been used in curries; in Japan, it is popularly served in tea; in Thailand, it is used in
`cosmetics; in China, it is used as a colorant; in Korea, it is served in drinks; in Malaysia, it is
`used as an antiseptic; in Pakistan, people use it as an anti-inflammatory agent to get relief
`from gastrointestinal discomfort; and in the United States, it is used in mustard sauce,
`cheese, butter, and chips, as a preservative and a coloring agent. Curcumin is marketed in
`several forms including capsules, tablets, ointments, energy drinks, soaps, and cosmetics.
`
`Our laboratory and others have shown that many other nutraceuticals in addition to
`curcumin have therapeutic potential against inflammatory conditions. Some of these
`nutraceuticals are resveratrol, ursolic acid, butein, silymarin, caffeic acid phenethyl ester,
`anethole, berberine, capsaicin, flavopiridol, thymoquinone, gossypin, withanolides, γ-
`tocotrienol, zerumbone, morin, plumbagin, and celastrol. Although these nutraceuticals have
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`been shown to exhibit anti-inflammatory activity, very little is known about their efficacy in
`humans. In the sections to follow, we review the biological activities of curcumin, with a
`special focus on its major activities at the molecular, cellular, animal, and human levels.
`BIOLOGICAL ACTIVITIES OF CURCUMIN
`Molecular level
`At the molecular level, curcumin has been shown to modulate a wide range of signaling
`molecules. Curcumin may cause upregulation or downregulation depending on the target
`and cellular context (Table 1). These targets fall into two categories: those to which
`curcumin binds directly and those whose activity curcumin modulates indirectly. Included
`among the indirect targets are transcription factors, enzymes, inflammatory mediators,
`protein kinases, drug resistance proteins, adhesion molecules, growth factors, receptors, cell-
`cycle regulatory proteins, cell-survival proteins, chemokines, and chemokine receptors
`(Table 1). Direct targets include inflammatory molecules, cell-survival proteins, protein
`kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I,
`xanthine oxidase, proteasomes, HIV1 integrase, HIV1 protease, sarco/endoplasmic
`reticulum Ca2+ ATPase, DNA methyltransferase 1, FtsZ protofilaments, carrier proteins, and
`metal ions. A comprehensive review of the molecular targets of curcumin and the molecular
`mechanisms involved can be found in numerous articles published by us and others (24–28).
`
`One of the most important targets of curcumin is pro-inflammatory transcription factors,
`such as NF-κB, activator protein-1, and signal transducer and activator of transcription
`(STAT) proteins (29). These transcription factors regulate the expression of genes that
`contribute to tumorigenesis, cell survival, cell proliferation, invasion, and angiogenesis.
`Curcumin has been shown to negatively regulate these transcription factors (29). Protein
`kinases are another major target of curcumin. For instance, the polyphenol has been shown
`to downregulate epidermal growth factor receptor and the activity of extracellular signal-
`regulated kinase 1/2 (also called mitogen-activated protein kinase) in pancreatic and lung
`adenocarcinoma cells (30). Curcumin has also been shown to inhibit the
`phosphatidylinositol 3 kinase/AKT pathway in malignant glioma cells (31). The polyphenol
`has been shown to completely inhibit the activity of several protein kinases, including
`phosphorylase kinase, protein kinase C, protamine kinase, autophosphorylation-activated
`protein kinase, and pp60c-src tyrosine kinase (29, 32).
`
`Cellular level
`Extensive in vitro studies over the past half century have shown that curcumin is a highly
`pleiotropic molecule and that its pleiotropic activity comes from its ability to modulate
`multiple signaling molecules. In particular, curcumin has been shown in numerous in vitro
`models to possess anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive,
`chemotherapeutic, anti-proliferative, wound healing, anti-nociceptive, anti-parasitic, and
`anti-malarial properties (Table 2).
`
`Inflammation is an integral component of many chronic diseases. The pro-inflammatory
`transcription factors NF-κB and signal transducer and activator of transcription 3 (STAT3)
`play a major role in mediating inflammatory response by modulating the production of pro-
`inflammatory cytokines (33, 34). Extensive research using a wide range of in vitro models
`over the past several years has indicated that curcumin can reduce inflammatory response by
`regulating the production of inflammatory molecules (35). For example, in one study,
`curcumin was shown to inhibit phorbol 12-myristate 13-acetate (PMA)-induced
`inflammation of mouse fibroblast cells (36). Curcumin has also been shown to act as an anti-
`inflammatory agent by inhibiting production of pro-inflammatory cytokines in PMA or
`lipopolysaccharide-stimulated peripheral blood monocytes and alveolar macrophages (37).
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`Our laboratory was the first to demonstrate that curcumin is a potent inhibitor of STAT3
`(38). The hydroxyphenyl unit in curcumin has been shown to be crucial to its anti-
`inflammatory activity (39). One study specifically identified the presence of a 4-
`hydroxyphenyl unit as crucial in this role; an increase in the anti-inflammatory activity was
`found by introducing additional small-sized alkyl or methoxy groups on the adjacent 3- and
`5-positions on the phenyl ring (40).
`
`Curcumin activity as an anti-oxidant and free-radical scavenger has been demonstrated from
`several in vitro studies. This activity can arise either from the hydroxyl group or the
`methylene group of the β-diketone (heptadiene-dione) moiety (41, 42). The importance of
`the phenolic hydroxyl group to curcumin's anti-oxidant activity is supported by several more
`studies (43–45). As shown in Table 2, curcumin has demonstrated anti-oxidant activities in
`blood plasma and platelets and in numerous cell lines. In one study, curcumin was shown to
`completely inhibit the in vitro production of superoxide anions, hydrogen peroxide, and
`nitrite radical production by rat macrophages (46). A recent study revealed that oxidative
`stimulation of G proteins in human brain membranes by the metabolic pro-oxidants
`homocysteine and hydrogen peroxide can be significantly depressed by curcumin (47). In
`another study, curcumin was shown to inhibit lipid peroxidation in a rat liver microsome
`preparation (48).
`
`Curcumin has been found to be cytotoxic to a variety of tumor cells. The action of curcumin
`depends on the cell type, the curcumin concentration, and the length of treatment. The major
`mechanism by which curcumin induces cytotoxicity is the induction of apoptosis. Curcumin
`also has the potential to inhibit cancer development and progression by targeting multiple
`steps in the process of tumorigenesis. It has activity both as a blocking agent, inhibiting the
`initiation step of cancer, and as a suppressing agent, inhibiting malignant cell proliferation
`during the promotion and progression of carcinogenesis (49). In addition to its role as a
`chemopreventive and chemotherapeutic agent, curcumin has been shown to have the
`potential to help eliminate chemoresistant cells by sensitizing tumors to chemotherapy, in
`part by inhibiting pathways that lead to treatment resistance (50). For example, adding
`curcumin to either 5-fluorouracil alone or 5-fluorourcil + oxaliplatin resulted in statistically
`significant growth inhibition and an enhancement in apoptosis in HCT116 and HT29 colon
`cancer cells (51). Similarly, many in vitro studies have supported the potential
`chemosensitizing ability of curcumin in multiple cancers and have provided evidence for
`curcumin's use singly or as an adjunct to current chemotherapeutic drugs (50). In addition to
`its role as a potentially potent chemosensitizer, curcumin is also a promising radiosensitizer
`in a wide variety of cancer cells (52–55). Curcumin has also been shown to suppress the
`growth of numerous cancer cells, including those from cancer cells of the prostate (56),
`biliary (57), pituitary gland (58), oral (59), and uterine leiomyoma (60).
`
`Curcumin possesses anti-microbial activities as well (61–64). For example, in a recent study
`of 14 Candida strains, curcumin displayed anti-fungal properties against all tested strains
`(62). In another study, curcumin was shown to improve the activity of common azole and
`polyene anti-fungals (65). In some cell culture systems, curcumin has been shown to possess
`anti-viral activities (63, 64). Other common activities of curcumin as demonstrated in in
`vitro cell culture models are wound healing in skin fibroblasts (66), anti-nociceptive activity
`in ganglion neurons (67), anti-parasitic activity against African trypanosomes (68),
`schistosomicidal activity against Schistosoma mansoni adult worms (69), anti-malarial
`activity (70), and nematocidal activity (71).
`
`Animal level
`
`Research carried out in animals during the past half century provides strong evidence for the
`beneficial role of curcumin against various diseases (41, 72, 73); the conditions in which
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`curcumin appears to be active are listed in Table 3. Most of these studies used rodents,
`although some used rabbits. For example, curcumin was shown to significantly reduce
`intestinal inflammation in multidrug resistance gene-deficient mice, which spontaneously
`develop colitis (74). In another study, curcumin was shown to attenuate colitis in the
`dinitrobenzene sulfonic acid-induced murine model of colitis (75). In a study investigating
`the protective effect of curcumin on trinitrobenzene sulfonic acid-induced colitis in mice,
`treatment with curcumin was associated with significant decreases in diarrhea and in
`disruption of the colonic architecture in mice (76). Finally, in a rat model, curcumin
`administration was associated with a significant reduction in chronic inflammation and
`inflammatory biomarkers (77).
`
`Curcumin has also been shown to improve the symptoms associated with diabetes. For
`example, in a streptozotocin-induced diabetic mouse model, curcumin (60 mg/kg body
`weight) was shown to act as an anti-diabetic agent and to maintain the normal structure of
`the kidney (78). The effect of curcumin on the progression of insulin resistance and type 2
`diabetes mellitus (T2DM) was investigated in another study. Insulin resistance and T2DM
`were induced in male Sprague Dawley rats by high-fat diet feeding for 60 and for 75 days.
`Curcumin was administered in the last 15 days of high-fat diet feeding after induction of
`insulin resistance and T2DM. Curcumin showed an anti-hyperglycemic effect and improved
`insulin sensitivity; these actions were attributed in part to its anti-inflammatory properties
`and anti-lipolytic effects. The authors concluded that curcumin could be a beneficial
`adjuvant therapy in T2DM (79). In T2DM mice, curcumin appeared to be a potent glucose-
`lowering agent, but it had no effect in non-diabetic mice (80).
`
`Obesity is a major risk factor for the development of T2DM, and curcumin's potential to
`prevent obesity was investigated in a mouse model. Mice were fed a high-fat diet (22% fat)
`supplemented with 500 mg curcumin/kg for 12 weeks. Supplementing the high-fat diet of
`mice with curcumin did not affect food intake, but it did reduce body weight gain, adiposity,
`and microvessel density in adipose tissue, which coincided with reduced expression of
`vascular endothelial growth factor and its receptor-2, peroxisome proliferator-activated
`receptor-γ, and CCAAT/enhancer-binding protein-α. These findings suggest that dietary
`curcumin may have the potential to prevent obesity (81).
`
`Curcumin has also been shown to affect various neurological disorders. In one study,
`curcumin treatment for 7 days was shown to reduce plaque formation and amyloid beta
`accumulation in a mouse model of Alzheimer's disease (82). In another mouse model,
`curcumin was shown to cross the blood-brain barrier, reduce amyloid levels and plaque
`burden, and exhibit significant activity against Alzheimer's disease (83). One of the
`pathological hallmarks of another prominent neurological disorder, Parkinson's disease, is
`the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the
`presynaptic soluble protein α-synuclein (84). Drug therapy for Parkinson's disease includes
`replacing or mimicking dopamine in the brain. Whether curcumin can be neuroprotective
`against a 6-hydroxydopamine model of Parkinson's disease was investigated in a rat model.
`Rats pretreated with curcumin showed a clear protection in dopamine levels in the striata of
`rat brain. Curcumin's ability to exhibit neuroprotection against 6-hydroxydopamine was
`related to its anti-oxidant capability and ability to penetrate into the brain (85). Another
`study evaluated the protective role of curcumin against dopaminergic neurotoxicity induced
`by MPTP or the 1-methyl-4-phenylpyridnium ion (MPP+) in C57BL/6N mice (86).
`Curcumin was shown to substantially improve behavioral deficits and enhance neuron
`survival in the substantia nigra in the MPTP-induced Parkinson's disease mouse model.
`Curcumin treatment was also associated with a significant inhibition of MPTP/MPP+-
`induced phosphorylation of c-Jun N-terminal kinase 1/2 and c-Jun. In addition, several other
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`studies using animal models have shown that curcumin has the potential to be active against
`Parkinson's disease (87, 88).
`
`Epilepsy is another chronic neurological disorder in which curcumin has shown promise. A
`recent study examined the effect of curcumin on pentylenetetrazole-induced seizure in a rat
`model. Rats pretreated with curcumin had less severe seizures and less cognitive impairment
`than those not pretreated (89). Curcumin exhibited anti-epileptic effects in another rat model
`in which seizure was induced by kainic acid treatment (90). Other neurological disorders in
`which curcumin has shown promise in animal models are diabetic encephalopathy (91),
`encephalomyelitis (92), intracerebral hemorrhage (93), spinal cord injury (94), cerebral
`malaria (95), convulsions (96), and brain ischemia (97).
`
`During the past two decades, our laboratory and others have demonstrated curcumin's
`potential as both a chemopreventive and a chemotherapeutic agent against cancer in rodent
`models. The chemopreventive efficacy of curcumin for colon cancer is particularly well
`established (98, 99). Other common cancers in which curcumin has shown protective effects
`in rodent models include esophageal (100), lung (101), kidney (102), stomach (103), liver
`(104), mouth (105), breast (106), bladder (107), leukemia (106), skin (108), small intestine
`(109), pancreatic (110), brain (111), and prostate (112) cancers. Accumulating evidence over
`the past several years has indicated that curcumin can be used for the treatment of
`established cancers as well. Most of these studies have used orthotopic or xenotransplant
`models and have employed curcumin either alone or in combination with existing therapies.
`Curcumin has shown potential for treatment of the following transplanted human cancers:
`cholangiocarcinoma (113), lymphoma (14), and melanoma (114), and prostate (115),
`pancreatic (116), colorectal (117), hepatocellular (118), breast (119), ovarian (120), and
`bladder (121) cancers.
`
`Mounting evidence over the past several years has indicated curcumin's efficacy in various
`animal models of psychiatric disorders. For example, in a mouse model of depression,
`curcumin exhibited anti-depressant activity that was potentiated by the concomitant
`administration of fluoxetine, venlafaxine, or bupropion (122). When curcumin (20 and 40
`mg/kg, intraperitoneally) was administered along with the bioavailability-enhancing agent
`piperine in these mice, enhancement of the anti-depressant action and increased brain
`penetration of curcumin were observed (122). Curcumin is also known to reverse olfactory
`bulbectomy-induced major depression in a rat model (123).
`
`Curcumin has also been investigated for its potential to reduce cancer-related symptoms
`such as fatigue, neuropathic pain, and cognitive deficit. For example, curcumin's ability to
`reduce immunologically induced fatigue was investigated in a mouse model (124).
`Reduction of chronic fatigue in these mice was associated with a marked decrease in serum
`tumor necrosis factor-α levels (124). In another mouse model, curcumin was found to
`reduce fatigue in association with decreases in the levels of interleukin-β, interleukin-6, and
`tumor necrosis factor-α in the soleus muscles (125). Another study explored the effect of
`curcumin against glutamate excitotoxicity, mainly focusing on the neuroprotective effects of
`curcumin on the expression of brain-derived neurotrophic factor (BDNF), which is involved
`in the development of depression (126). Exposure of rat cortical neurons to 10 μM
`glutamate for 24 h caused a significant decrease in the BDNF level, accompanied by
`reduced cell viability and enhanced cell apoptosis. Pretreatment of neurons with curcumin
`prevented the declines in BDNF expression and cell viability in a dose- and time-dependent
`manner. The study concluded that the neuroprotective effects of curcumin might be
`mediated through the BDNF signaling pathway (126). An investigation into the role of
`curcumin in reducing neuropathic pain in mice with streptozotocin-induced diabetes found
`that treating mice with insulin in combination with curcumin significantly reduced diabetic
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`neuropathic pain that was associated with a reduction in tumor necrosis factor-α level (127).
`Curcumin has also been shown to improve cognitive function in animal models. One study
`investigated the effect of curcumin on cognitive function and inflammation in diabetic rats.
`These rats exhibited cognitive deficits in association with enhancements in serum tumor
`necrosis factor-α levels, which were significantly attenuated after chronic treatment with
`curcumin (60 mg/kg) (91).
`
`In addition to the activities discussed above, curcumin has shown potential activity against
`numerous other disorders and diseases, including those of eyes, lungs, liver, kidneys, and
`gastrointestinal and cardiovascular systems, as well as conditions such as fibrosis, wound
`healing problems, aging, asthma, endometriosis, and muscle wasting. The potential of
`curcumin to enhance memory and ameliorate morphine addiction has also been reported.
`
`Curcumin analogues have also shown potential against animal models of human diseases.
`One study examined the effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione, a
`bisdemethoxycurcumin analog (BDMC-A) on 1,2-dimethylhydrazine (DMH)-induced colon
`carcinogenesis in male Wistar rats (128). The study also compared the efficacy of BDMC-A
`with that of curcumin. Both BDMC-A and curcumin were equipotent in inhibiting the
`DMH-induced colon tumor incidence and normalizing histological changes. The study
`concluded that the presence of a terminal phenolic group and the conjugated double bonds in
`the central seven-carbon chain could be responsible for the agents' beneficial effects (128).
`In another study, curcumin and demethoxycurcumin were shown to reduce lead-induced
`memory deficits in male Wistar rats (129). In addition, tetrahydrocurcumin, another
`analogue of curcumin, has been shown to reduce the development of preneoplastic aberrant
`crypt foci initiated by 1,2-dimethylhydrazine dihydrochloride in the colons of mice (99).
`THC has also been shown to ameliorate oxidative stress-induced renal injury in mice (130).
`The anti-diabetic activity of THC in streptozotocin-nicotinamide-induced diabetes in rats
`has been investigated (131), and in one study, THC was found to possess more potent anti-
`diabetic activity than curcumin in type 2 diabetic rats (132).
`
`Preclinical data obtained over the past several years have provided a strong foundation for
`testing curcumin's potential in human subjects. To date, approximately 50 clinical trials
`using human subjects have been completed. Although still in the initial phases, most of these
`trials have suggested that curcumin is safe and effective in a number of human diseases (Fig
`2). The most promising effects of curcumin have been observed with cancer; inflammatory
`conditions; skin, eye, and neurological disorders; diabetic nephropathy; and pain.
`
`In one of the early studies, curcumin was found to produce remarkable symptomatic relief in
`62 patients with external cancerous lesions. The effect continued for several months in many
`patients, and an adverse reaction was noticed in only one patient (133).
`
`A phase II clinical trial from our group evaluated the efficacy of oral curcumin in 25 patients
`with advanced pancreatic cancer. Patients received 8 g curcumin daily until disease
`progression, with disease restaging done every 2 months. Circulating curcumin was
`detectable in both glucuronide and sulfate conjugate forms, albeit at low steady-state levels,
`suggesting poor oral bioavailability. Two patients showed clinical biological response to
`curcumin; nevertheless, one additional patient showed a brief but marked tumor regression
`by 73%, and one patient had disease stability for >18 months. None of the patients showed
`toxic effects from curcumin. We concluded that oral curcumin is well tolerated and has
`biological activity in some patients with pancreatic cancer (134).
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`In some clinical trials, curcumin has been found to be useful in combination with existing
`drugs for pancreatic cancer patients. For example, one study evaluated the activity and
`feasibility of gemcitabine and curcumin combinations in patients with advanced pancreatic
`cancer. Seventeen patients who enrolled in the study were given 8 g curcumin by mouth
`daily, concurrently with gemcitabine (1000 mg/m2, intravenously, three times a week for 4
`weeks). Five patients discontinued curcumin after a few days to 2 weeks because of
`intractable abdominal fullness or pain. In two other patients, the dose of curcumin was
`reduced to 4 g/day because of abdominal complaints. One of 11 evaluable patients had a
`partial response, 4 had stable disease, and 6 had tumor progression. Time to tumor
`progression was 1–12 months (median, 2.5 months), and overall survival was 1–24 months
`(median, 5 months). It was concluded that low compliance for curcumin at a dose of 8 g/day,
`when taken with systemic gemcitabine, may prevent the use of high doses of oral curcumin
`needed to achieve a systemic effect (135).
`
`A phase I/II study also evaluated the safety and efficacy of a combination therapy of
`curcumin with gemcitabine for pancreatic cancer. The study enrolled 21 patients with
`gemcitabine-resistant disease; they received 8 g oral curcumin daily in combination with
`gemcitabine. The primary endpoint was safety for the phase I portion of the trial and the
`feasibility of oral curcumin for phase II. The phase I portion of the study revealed the
`absence of limiting toxicities, and 8 g/day oral curcumin was selected as the recommended
`dose for the phase II portion. Curcumin was found to be well tolerated in this phase as well,
`and the plasma curcumin concentration ranged from 29 to 412 ng/ml in the five patients
`tested. It was concluded that combination therapy using 8 g oral curcumin daily with
`gemcitabine is safe and feasible for patients with pancreatic cancer (136). Other common
`cancers in which curcumin has shown efficacy either alone or in combination with existing
`drugs include prostate cancer, breast cancer, multiple myeloma, and adenoma.
`
`The role of curcumin in improving body weight was evident from a recent study of patients
`with colorectal cancer. Curcumin administration (360 mg/day for 10–30 days) in these
`patients significantly improved body weight; the effect of curcumin was associated with a
`significant decrease in serum tumor necrosis factor-α levels (137).
`
`Curcumin has shown promise against cardiac conditions as well. For example, one study
`evaluated the efficacy of curcumin in reducing lipid content in patients with acute coronary
`syndrome. Seventy-five patients with acute coronary syndrome participated in the study, and
`curcumin was administered at three different doses: low (15 mg/day, three times a day),
`moderate (30 mg/day, three times a day), and high (60 mg/day, three times a day). The
`effect of curcumin administration on total cholesterol, low-density lipoprotein cholesterol,
`high-density lipoprotein cholesterol, and triglyceride levels was investigated. Interestingly,
`curcumin was found to be more effective at low doses than at high doses in reducing total
`cholesterol and low-density lipoprotein cholesterol levels in these patients (138).