Elsevier

Current Problems in Cancer

Volume 31, Issue 4, July–August 2007, Pages 243-305
Current Problems in Cancer

Role of Curcumin in Cancer Therapy

https://doi.org/10.1016/j.currproblcancer.2007.04.001Get rights and content

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

First page preview

First page preview
Click to open first page preview

References (289)

  • A.R. Shahed et al.

    Quercetin and curcumin up-regulate antioxidant gene expression in rat kidney after ureteral obstruction or ischemia/reperfusion injury

    Transplant Proc

    (2001)
  • S. Awasthi et al.

    Curcumin protects against 4-hydroxy-2-trans-nonenal-induced cataract formation in rat lenses

    Am J Clin Nutr

    (1996)
  • S. Shishodia et al.

    Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma

    Biochem Pharmacol

    (2005)
  • D.K. Giri et al.

    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

    (1998)
  • A.C. Bharti et al.

    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

    (2003)
  • S. Singh et al.

    Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane)

    J Biol Chem

    (1995)
  • S. Philip et al.

    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

    (2003)
  • R.M. Weber-Nordt et al.

    Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines

    Blood

    (1996)
  • M. Karin et al.

    AP-1 function and regulation

    Curr Opin Cell Biol

    (1997)
  • Y.R. Chen et al.

    Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin

    Oncogene

    (1998)
  • M. Tomita et al.

    Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines

    Leukoc Res

    (2006)
  • C. Polytarchou et al.

    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

    (2005)
  • M.L. Cho et al.

    Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways

    Immunol Lett

    (2006)
  • B. Brouk

    Plants Consumed by Man

    (1975)
  • R.C. Srimal et al.

    Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent

    J Pharm Pharmacol

    (1973)
  • H.P. Ammon et al.

    Pharmacology of Curcuma longa

    Planta Med

    (1991)
  • S.K. Jain et al.

    Medicinal Plants of India

    (1991)
  • A.K. Nadkarni
    (1954)
  • T.N. Patil et al.

    Hypocholesteremic effect of curcumin in induced hypercholesteremic rats

    Ind J Exp Biol

    (1971)
  • K.K. Soudamini et al.

    Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin

    Ind J Physiol Pharmacol

    (1992)
  • K.B. Soni et al.

    Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers

    Ind J Physiol Pharmacol

    (1992)
  • M.S. Hussain et al.

    Effect on curcumin on cholesterol gall-stone induction in mice

    Ind J Med Res

    (1992)
  • K.A. Naidu et al.

    Inhibition of human low density lipoprotein oxidation by active principles from spices

    Mol Cell Biochem

    (2002)
  • B.S. Patro et al.

    Protective activities of some phenolic 1,3-diketones against lipid peroxidation: possible involvement of the 1,3-diketone moiety

    Chembiochem

    (2002)
  • R. Srivastava et al.

    Effect of curcumin on platelet aggregation and vascular prostacyclin synthesis

    Arzneimittelforschung

    (1986)
  • M. Dikshit et al.

    Prevention of ischaemia-induced biochemical changes by curcumin and quinidine in the cat heart

    Ind J Med Res

    (1995)
  • C. Nirmala et al.

    Protective role of curcumin against isoproterenol induced myocardial infarction in rats

    Mol Cell Biochem

    (1996)
  • N. Venkatesan

    Curcumin attenuation of acute adriamycin myocardial toxicity in rats

    Br J Pharmacol

    (1998)
  • M. Srinivasan

    Effect of curcumin on blood sugar as seen in a diabetic subject

    Ind J Med Sci

    (1972)
  • P.S. Babu et al.

    Influence of dietary curcumin and cholesterol on the progression of experimentally induced diabetes in albino rat

    Mol Cell Biochem

    (1995)
  • P.S. Babu et al.

    Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats

    Mol Cell Biochem

    (1997)
  • P. Suresh Babu et al.

    Amelioration of renal lesions associated with diabetes by dietary curcumin in streptozotocin diabetic rats

    Mol Cell Biochem

    (1998)
  • N. Arun et al.

    Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats

    Plant Foods Hum Nutr

    (2002)
  • S.D. Deodhar et al.

    Preliminary study on antirheumatic activity of curcumin (diferuloyl methane)

    Ind J Med Res

    (1980)
  • C. Natarajan et al.

    Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes

    J Immunol

    (2002)
  • G.P. Lim et al.

    The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse

    J Neurosci

    (2001)
  • C.J. Li et al.

    Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication

    Proc Natl Acad Sci U S A

    (1993)
  • W.C. Jordan et al.

    Curcumin: a natural herb with anti-HIV activity

    J Natl Med Assoc

    (1996)
  • A. Mazumder et al.

    Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanisms of drug action

    J Med Chem

    (1997)
  • G.S. Sidhu et al.

    Enhancement of wound healing by curcumin in animals

    Wound Repair Regen

    (1998)
  • Cited by (384)

    View all citing articles on Scopus

    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).

    View full text