Role of Curcumin in Cancer Therapy
Section snippets
Why Does Curcumin Have Anticancer Effects?
Cancer is a hyperproliferative disorder marked by metastasis into the vital organs of the body through invasion and angiogenesis. Curcumin blocks the transformation, proliferation, and invasion of tumor cells. The biochemical pathways involved in the carcinogenesis process have been investigated extensively over the last four decades. Numerous studies over the last two decades have demonstrated that curcumin targets several steps in these biochemical pathways, thus showing immense promise for
Molecular Targets of Curcumin
Carcinogenesis is a multistep process in which several biochemical pathways and hundred of molecules are deregulated. These include the growth factors, growth factor receptors, transcription factors, cytokines, enzymes, and genes regulating apoptosis and proliferation. Curcumin has been shown to target several of the molecules involved in carcinogenesis, as described in the following sections (Fig 1).
Antiproliferative Effects
Curcumin suppresses the growth and proliferation of a wide variety of tumor cell lines of different tissue origins. The antiproliferative effect of curcumin is dependent on the cell type, concentration of curcumin, and duration of treatment. Curcumin inhibits the proliferation of tumor cells by suppressing the cell cycle regulatory proteins. Several proteins are known to regulate the timing of the events in the cell cycle, and loss of this regulation is the hallmark of cancer. Major control
Apoptotic Effects
Apoptosis helps to establish a natural balance between cell death and cell renewal in mature animals by destroying excess, damaged, or abnormal cells. The balance between survival and apoptosis, however, often tips toward the former in cancer cells. The major mechanism by which curcumin induces cytotoxicity in tumor cells is induction of apoptosis. Curcumin decreases the expression of antiapoptotic members of the Bcl-2 family and elevates the expression of p53, Bax, and procaspases-3, -8, and
Chemokines and Metastasis
Chemokines are small, chemotactic cytokines that direct migration of leukocytes, activate inflammatory responses, and participate in regulation of tumor growth. Most chemokines are expressed in response to a stimulus, but some are constitutively expressed in a tissue-specific manner. Chemokines exert their migration-inducing properties on leukocytes through binding to chemokine receptors. IL-8 (CXCL8) was the first chemokine discovered to stimulate endothelial cell chemotaxis, proliferation,
Angiogenesis
Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into a cancerous growth, supplying nutrients and oxygen and removing waste products. For most solid tumors, angiogenesis is essential for tumor growth and metastasis.215 Tumor angiogenesis actually starts with cancerous tumor cells releasing molecules that send signals to surrounding normal host tissue. More than a dozen different proteins (eg, bFGF, EGF, granulocyte colony-stimulating factor, IL-8, PDGF,
Chemosensitizing Effects
Chemosensitivity is the susceptibility of tumor cells to the cell-killing effects of anticancer drugs. Most of the chemotherapeutic agents frequently induce drug resistance. HER2, a growth factor receptor overexpressed in breast cancer, has been implicated in paclitaxel-induced resistance, probably through activation of NF-κB. Acquired resistance to chemotherapetic agents is most likely mediated through a number of mechanisms, including the multidrug resistance (MDR) protein. Multidrug
Radiosensitizing Effects
Radiotherapy plays an important role in the management of cancers. Radiotherapy helps in achieving local control of tumors following surgery in patients with early stage cancer, but radiotherapy alone fails to suppress the tumors that recur and become radioresistant. The factors governing radioresistance in patients whose cancer recurs are still not clear. Several studies have shown that curcumin sensitizes tumor cells to radiation therapy.
Chendil and coworkers investigated the radiosensitizing
Radioprotective Effects
Findings of several studies suggest that curcumin is radioprotective. Oral administration of curcumin at doses of 5, 10, or 20 mg/kg of body weight significantly reduced the frequencies of micronucleated polychromatic erythrocytes in mice that underwent whole-body exposure to 1.15 Gy or 0.05 Gy/s of gamma-radiation at 24, 30, or 48 hours postirradiation. This effect was observed after a single administration of curcumin either 2 hours before or immediately after irradiation.243 Thresiamma and
In Vivo Studies
Several animal models have been employed to investigate the antitumor and anticarcinogenic effects of curcumin. The mechanisms by which curcumin suppresses carcinogenesis have been investigated in several animal tumor systems, including skin, colon, lung, duodenum, stomach, esophagus, and oral cavity.
Kuttan and coworkers175 examined the anticancer potential of curcumin in vivo by using Dalton’s lymphoma cells grown as ascites in mice. Initial experiments indicated that curcumin reduced the
Clinical Trials with Curcumin
Several pilot clinical trials have been reported using curcumin (Table 1). There are additional phase II clinical trials for various diseases with curcumin that are ongoing (Table 2). Despite its proven safety over centuries of use in south Asian countries, over a dozen clinical studies evaluating the safety and efficacy of curcumin in humans have already been reported. Phase I study of curcumin in humans was reported by Cheng and coworkers in 2001. These investigators examined the toxicology,
Conclusion
The exhaustive research and numerous investigations carried over the last few decades suggest that curcumin has great potential in the prevention and cure of cancer. Curcumin modulates several biochemical pathways and numerous targets involved in carcinogenesis. Phase I clinical trials have revealed that up to 8 g of curcumin per day for 3 months is well tolerated in humans, although the optimum dose that can be administered for therapy is still unclear. Orally administered curcumin has poor
References (289)
- et al.
Effect of curcumin on serum and liver cholesterol levels in the rat
J Nutr
(1970) The influence of turmeric and curcumin on cholesterol concentration of eggs and tissues
Poult Sci
(1976)- et al.
Dietary curcuminoids prevent high-fat diet-induced lipid accumulation in rat liver and epididymal adipose tissue
J Nutr
(2001) - et al.
Oral administration of a turmeric extract inhibits LDL oxidation and has hypocholesterolemic effects in rabbits with experimental atherosclerosis
Atherosclerosis
(1999) - et al.
Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets
Prostaglandins Leukot Essent Fatty Acids
(1995) - et al.
Anti-thrombotic effect of curcumin
Thromb Res
(1985) - et al.
Effect of curcumin on certain lysosomal hydrolases in isoproterenol-induced myocardial infarction in rats
Biochem Pharmacol
(1996) - et al.
Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology
Neurobiol Aging
(2001) - et al.
Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes
Bioorg Med Chem
(1993) - et al.
Curcumin and curcumin derivatives inhibit Tat-mediated transactivation of type 1 human immunodeficiency virus long terminal repeat
Res Virol
(1998)
Quercetin and curcumin up-regulate antioxidant gene expression in rat kidney after ureteral obstruction or ischemia/reperfusion injury
Transplant Proc
Curcumin protects against 4-hydroxy-2-trans-nonenal-induced cataract formation in rat lenses
Am J Clin Nutr
Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma
Biochem Pharmacol
Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cellsAutocrine role of tumor necrosis factor and reactive oxygen intermediates
J Biol Chem
Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis
Blood
Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane)
J Biol Chem
Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha /IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways
J Biol Chem
Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines
Blood
AP-1 function and regulation
Curr Opin Cell Biol
Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin
Oncogene
Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines
Leukoc Res
Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein-1 and up-regulation of the heparin affin regulatory peptide gene
J Biol Chem
Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways
Immunol Lett
Plants Consumed by Man
Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent
J Pharm Pharmacol
Pharmacology of Curcuma longa
Planta Med
Medicinal Plants of India
Hypocholesteremic effect of curcumin in induced hypercholesteremic rats
Ind J Exp Biol
Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin
Ind J Physiol Pharmacol
Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers
Ind J Physiol Pharmacol
Effect on curcumin on cholesterol gall-stone induction in mice
Ind J Med Res
Inhibition of human low density lipoprotein oxidation by active principles from spices
Mol Cell Biochem
Protective activities of some phenolic 1,3-diketones against lipid peroxidation: possible involvement of the 1,3-diketone moiety
Chembiochem
Effect of curcumin on platelet aggregation and vascular prostacyclin synthesis
Arzneimittelforschung
Prevention of ischaemia-induced biochemical changes by curcumin and quinidine in the cat heart
Ind J Med Res
Protective role of curcumin against isoproterenol induced myocardial infarction in rats
Mol Cell Biochem
Curcumin attenuation of acute adriamycin myocardial toxicity in rats
Br J Pharmacol
Effect of curcumin on blood sugar as seen in a diabetic subject
Ind J Med Sci
Influence of dietary curcumin and cholesterol on the progression of experimentally induced diabetes in albino rat
Mol Cell Biochem
Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats
Mol Cell Biochem
Amelioration of renal lesions associated with diabetes by dietary curcumin in streptozotocin diabetic rats
Mol Cell Biochem
Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats
Plant Foods Hum Nutr
Preliminary study on antirheumatic activity of curcumin (diferuloyl methane)
Ind J Med Res
Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes
J Immunol
The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse
J Neurosci
Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication
Proc Natl Acad Sci U S A
Curcumin: a natural herb with anti-HIV activity
J Natl Med Assoc
Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanisms of drug action
J Med Chem
Enhancement of wound healing by curcumin in animals
Wound Repair Regen
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Supported by funds from the Clayton Foundation for Research (to BBA), a Department of Defense US Army Breast Cancer Research Program grant (BC010610, to BBA), a P01 grant (CA-91844) on lung cancer chemoprevention from the National Institutes of Health (to BBA), a P50 Head and Neck Cancer SPORE grant from the National Institutes of Health (to BBA), and Cancer Center Core Grant CA-16672 (to BBA).