Curcumin and Cancer

Curcumin inhibits the growth of various cancer cells

Curcumin and cancer: an "old-age" disease with an "age-old" solution.
Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB.
Cancer Lett. 2008 Aug 18;267(1):133-64.

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Curcumin inhibits different stages of cancer progression

From Anticancer potential of curcumin: preclinical and clinical studies.
Aggarwal BB, Kumar A, Bharti AC.
Anticancer Res. 2003 Jan-Feb;23(1A):363-98.

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Curcumin Downregulates Expression of Cell Proliferation, Antiapoptotic and Metastatic Gene Products Through Suppression of IκBa Kinase and AKT Activation

Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB.
Molecular Pharmacology, 2006, 69(1):195-206

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Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins

Kunnumakkara AB, Anand P, Aggarwal BB.
Cancer Letters
2008, 269(2):199-225

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Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydro-curcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism

Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G, Limtrakul P, Badmaev V, Aggarwal BB.
Carcinogenesis.
2007, 28(8):1765-73

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Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines

Aggarwal BB, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G
Biochemical Pharmacology
2007, 73(7):1024-32

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Role of pro-oxidants and anti oxidants in the anti-inflammatory and apoptotic effects of Curcumin (diferuloylmethane)

Sandur SK, Ichikawa H, Pandey MK, Kunnumakkara AB, Sung B, Sethi G, Aggarwal BB.
Free Radical Biology & Medicine
2007, 43(4):568-80

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Curcumin prevents cancer in animals

Cancer	Carcinogen	Animal	Dose	Reference
Gastrointestinal cancers:
ACF	AOM	Rat	2000 ppm	Rao et al, 1993
Colon cancer	AOM	Mice	0.5 to 0.2% w/w	Huang et al, 1994
Colon cancer	DMH	Mice	0.5%	Kim et al, 1998
Colon cancer	AOM	Rat	2000 ppm	Rao et al, 1995
Colon cancer	AOM	Rat	0.2 or 0.6% w/w	Kawamori et al, 1999
Colon cancer	PhlP	Apc mice	2000 ppm	Collett et al, 2001
Colon cancer	AOM	Rat	1 or 2% w/w	Pereira et al, 1996
Colon cancer	AOM	Rat	0.6% w/w	Kwon et al, 2004
Colon cancer	DMH	Rat	0.6%	Shiptz B, 2006
Colitis	TNBS	Mice	0.5-5%, diet	Sugimoto K, 2002
Colitis	DNB	Mice	0.25%, diet	Salh B, 2003
Colitis	TNBS	Mice	50 mg/kg	Ukil A, 2003
Ulcerative colitis	TNCB	Rat	30-60 mg/kg	Jung H, 2006
Ulcerative colitis	DNCB	Rat	25-100 mg/kg	Venkatarangana MV, 2007
Duodenal Tumor	MNNG	Mice	0.5 to 2.0% w/w	Huang et al, 1994
Esophageal cancer	NMBA	Rat	500 ppm	Usida et al, 2000
FAD*	AOM	Mice	2%	Huang et al, 1992
FAP*	---	Min/+ mice	0.1, 0.2, or 0.5% w/w	Perkins et al, 2002
Forestomach neoplasia	B[a]P	Mice		Azuine et al, 1992
Forestomach cancer	B[a]P	Mice	2% w/w	Singh et al, 1998
Forestomach neoplasia	B[a]P	Mice		Nagabhushan et al, 1992
Stomach cancer	MNNG	Rat	0.05% w/w	Ikezaki et al,
Liver cancers:
Hepatic hyperplasia	DNM	Rat	200 or 700 mg/kg	Chuang et al, 2000
Liver cancer	DNM	Mice	0.2% w/w	Chuang et al, 2000
Lung cancers:
Lung Cancer	B[a]P & NNK	A/J mice	2000 ppm	Hecht et al, 1999
Blood cancers:
Lymphoma/leukemia	DMBA	Sencar mice	2% w/w	Huang et al, 1998
Breast cancers:
Mammary tumor	DMBA	Rat	0.8 to 1.6% w/w	Pereira et al, 1996
Mammary tumor	DMBA	Rat	50 to 200 mg/kg	Singletary et al, 1996
Mammary tumor	DMBA	Rat	1% w/w	Deshpande et al, 1998
Mammary tumor	DMBA	Sencar mice	2% w/w	Huang et al, 1998
Mammary tumor	γ-radiation	Rat		Inano et al, 1999
Mammary tumor	γ-radiation	Rat	1% w/w	Inano et al, 2002
Mammary tumor	DMBA	Rat		Lin et al, 2001
Mammary tumor	DMBA	Sencar mice		Lin et al, 2001
Mammary tumor	γ-radiation	Rat		Inano et al, 2002
Oral cancers:
Oral cancer	MNA	Hamster		Azuine et al, 1992
Oral cancer	NQO	Rat	500 ppm	Tanaka et al, 1994
Prostate cancers:
Prostate cancer	DMAB & PhlP	Rat	15 to 500 ppm	Imaida et al, 2001
Skin cancers:
Dermatitis	TPA + UV-A	Mice		Ishizaki et al, 1996
Skin tumor	TPA	Mice		Huang et al, 1988
Skin tumor	DMBA	Mice		Azuine et al, 1992
Skin tumors	TPA	Mice	10 & 30 mmol	Lu et al, 1993
Skin tumor	TPA	Mice		Huang et al, 1995
Skin tumor	TPA	Mice	1, 10, 100 or 3000 nmol	Huang et al, 1997
Skin tumor		Mice		Soudamini, 1989
Skin tumor	DMBA	Mice		Nagabhushan et al, 1992
Skin tumor	B[a]P and DMBA	Mice		Huang et al, 1992
Other cancers:
Multi-organ cancer	DHPN, EHEN	Rat	1% w/w	Takaba et al, 1997

From Anticancer potential of curcumin: preclinical and clinical studies.
Aggarwal BB, Kumar A, Bharti AC.
Anticancer Res. 2003 Jan-Feb;23(1A):363-98.

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Treatment of cancer by curcumin in animals

Tumor	Route	Dose	Model	References
Ascites2	IP	50 mg/kg	Ascites	Kuttan et al, 1985
Ascites	IP	50 mg/kg	Ascites	Ruby et al, 1995
Breast1	Diet	2% w/w	Orthotopic	Aggarwal et al, 2006
Breast1	Diet	1% w/w	Orthotopic	Bachmeier et al, 2007
Colon2	IV	40 mg/kg	Orthotopic	Li et al, 2007
Gastric cancer	Oral	50-200 mg/kg	Xenograft	Cui et al, 2006
Gliobalstoma	IT	10 mg/kg	Orthotopic	Aoki et al, 2007
HCC3		100-200 mg/kg	Orthotopic	Ohashi et al, 2003
Hepatoma	Oral	50-200 mg/kg	Xenograft	Cui et al, 2006
HNSCC	Sub cute	50-250 μmol/L	Xenograft	LoTempio et al, 2005
Leukemia	Oral	50-200 mg/kg	Xenograft	Cui et al, 2006
Melanoma	IP	25 mg/kg	Xenograft	Odot et al, 2004
Ovarian	IP	500 mg/kg	Orthotopic	Lin et al, 2007
Pancreas	IV	40 mg/kg	Xenograft	Li et al, 2005
Pancreas	Gavage	1 gm/kg	Orthotopic	Kunnumakkara et al, 2005
Prostate	Diet	2% w/w	Xenograft	Dorai et al, 2001
Prostate	Gavage	5 mg/kg	Orthotopic	Hong et al, 2006
Prostate	Gavage	5 mg/day	Xenograft	Li et al, 2007
Colorectal cancer	Gavage	1 gm/kg	Orthotopic	Kunnumakkara et al, 2008

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1. Lung metastases; 2. Liposomal curcumin; 3. Intrahepatic metastatis; IP - intraperitoneal; IT - intratumoral; IV - intravenous

Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic.
Biochem Pharmacol. 2008 Feb 15;75(4):787-809.

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Role of Curcumin in cancer therapy

Shishodia S, Chaturvedi MM, Aggarwal BB.
Current Problems in Cancer
2007, 31(4):243-305

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Curcumin as "Curecumin": from kitchen to clinic

Goel A, Kunnumakkara AB, Aggarwal BB.
Biochemical Pharmacology
2008, 75(4):787-809

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Curcumin inhibits constitutive NF-κB, IκBα kinase, inhibits proliferation, and induces apoptosis in human multiple myeloma cells

Bharti A., Donato N., Singh S., Aggarwal B.B.
BLOOD, 2003, 101: 885-61

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Nuclear Factor-κB and STAT3 are Constitutively Active in CD138+ Cells Derived from Multiple Myeloma Patients and Their Suppression Leads to Apoptosis

Alok C. Bharti, Shishir Shishodia, James M. Reuben, Donna Weber, Raymond Alexanian, Saroj Raj-Vadhan, Zeev Estrov, Moshe Talpaz and Bharat B. Aggarwal
BLOOD, 2004, 103: 3175-84

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Curcumin the golden pill!

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Curcumin downregulates NF-κB and related genes in patients with multiple myeloma: Results of a phase 1/2 study

S. Vadhan-Raj, D.Weber, M.Wang, S. Giralt, R. Alexanian, S. Thomas, X. Zhou, P. Patel,C. Bueso-Ramos, R. Newman, B. Aggarwal.

Objectives: To evaluate the safety, clinical tolerance, and biologic effects of curcumin in MM pts who had asymptomatic, relapsed, or plateau phase disease.

Curcumin alone (administered orally at 2,4,6,8, or 12 gms/day in 2 divided doses) or in combination with Bioperine (10 mg in 2 divided doses) was administered for 12 weeks in MM pts.

Blood was collected before and after treatment with curcumin for limited PK/PD and PBMCs were examined for expression of NF-κB (p65), COX-2 and phospho-STAT3 as surrogate biomarkers.

Treatment with curcumin and a fixed dose of bioperine has been well tolerated, with no significant adverse events. Of the 29 evaluable pts treated so far, 12 patients have continued treatment for more than 12 weeks and 5 (1 pt at 4 gms, 2 at 6 gms, and 2 at 8 gms dose levels) have completed full one year of treatment with stable disease.

PBMC from 28 cancer pts examined at baseline showed constitutively active NF-κB (mean + STD, 74.2 % + 14.0 positive cells), COX2 (66 % + 15.4), and STAT3 (52.8 % + 19.2). Oral adminisitration of curcumin significantly downregulated the constitutive activation of NF-κB (p<0.0001) and STAT3 (p<0.0001), and suppressed COX2 (p<0.001) expression in most of the patients.

Conclusions: This is the first report to indicate that curcumin, a highly safe agent, is bioavailable and can downregulate NF-κB, STAT3 and COX2 in MM pts and suggests a potential therapeutic role that can be further investigated.

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Constitutive activation of NF-κB in PBMC from MM Patients and its Suppression by Curcumin (2g/day)

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Curcumin inhibits proteasomal activity

• Curcumin can inhibit the activation of proteasome which causes IκBα degradation (Singh etal, 1995)
• Curcumin can inhibit the activation of proteosome which causes HDAC2 degradation (Meja etal, 2008)
• Curcumin can inhibit the proteasome activity which blocks sepsis-induced muscle proteolysis in rats (Poylin V et al 2008)
• Curcumin can reduce the 20S proteasome proteolytic activities which leading to increased accumulation of ubiquitinated proteins by coxsackievirus (Si X et al 2007)
• Curcumin can reduce the proteosomal activity which promotes mutant huntingtin-induced cell death (Dikshit P et al 2006)
• Curcumin can attenuate the expression of 20S proteasome α-subunit and E214k induced by PIF in C2C12 myoblasts (Wyke SM et al 2004)
• Curcumin inhibited the proteosomal function which induced apoptosis through mitochondrial pathway in mouse neuro 2a cells (Jana NR etal 2004)
• Curcumin blocked ubiquitin-26S proteasome-dependent p53 degradation induced by human papilloma virus protein E6 through inhibition of CSN kinase in reticulocyte lysates (Bech-Otschir D et al 2001)

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AP-1, activator-protein 1; ARNT, aryl hydrocarbon receptor nuclear translocator; C/EBP, CCAAT-enhancer-binding proteins; CBP, cAMP response element-binding (CREB)-binding protein; COP9, constitutive photomorphogenic 9; COX-2, cyclooxygenase-2; HDAC2, histone deacetylase 2; NF-κB, nuclear factor-kappaB; PIF, proteolysis-inducing factor; Sp1, specificity protein 1

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Curcumin stimulates proteasomal activity

• Curcumin induced proteasome-dependent down-regulation of Sp1, Sp3, and Sp4 in 253JB-V and KU7 cells (Chanalapaka etal, 2008)
• Curcumin induces down-regulation of cyclin D and cyclin E through 26S proteasome (Srivastava, 2007)
• Curcumin stimulates proteasome-dependent degradation of COX-2 through inhibition of COP9 signalosome (CSN)-associated kinases in HeLa cells (Neuss H et al, 2007)
• Curcumin induced proteasome-dependent down-regulation of cyclin E in various human cancer cell lines (Aggarwal, 2007)
• Curcumin can induce the activation of proteasome which causes AP-1 degradation (Balasubramania, 2007)
• Curcumin stimulated proteosomal degradation of ARNT in Hep3B cells (Choi H et al 2007)
• Curcumin showed biphasic hrmetic dose–response with respect to proteasome activity in keratinocytes (Ali RE, 2006)
• Curcumin promoted proteasome-dependent degradation of p300 and CBP proteins in the cells and inhibited the acetyltransferase activity of purified p300 (Marcu MG et al, 2006)
• Curcumin can induce the activation of proteasome which causes degradation and suppression of C/EBP factor (Balasubramanian and Eckert, 2004)
• Curcumin, the inhibitors of CSN associated kinase, can induce ubiquitination and proteasome-dependent degradation of transiently expressed Id3 in HeLa cells (Berse M et al 2004)

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AP-1, activator-protein 1; ARNT, aryl hydrocarbon receptor nuclear translocator; C/EBP, CCAAT-enhancer-binding proteins; CBP, cAMP response element-binding (CREB)-binding protein; COP9, constitutive photomorphogenic 9; COX-2, cyclooxygenase-2; HDAC2, histone deacetylase 2; NF-κB, nuclear factor-kappaB; PIF, proteolysis-inducing factor; Sp1, specificity protein 1

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Curcumin circumvents chemo resistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model

Sung B, Kunnumakkara AB, Sethi G, Anand P, Guha S, Aggarwal BB.
Molecular Cancer Therapeutics 2009, 8(4):959-70

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Curcumin potentiates the effect of velcade (ps341) against human multiple myeloma U266 cells

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Curcumin potentiates the effect of thalidomide against human multiple myeloma U266 cells

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Curcumin inhibits TNF-mediated NF-κB activation leading to suppression of expression of cell surface adhesion molecules in endothelial cells

Kumar A. and Aggarwal B. B.
Biochemical Pharmacology 55: 775-783, 1998

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Curcumin inhibits cyclin D1 expression through transcriptional and post-transcriptional regulation

Mukhopadhyay A, Banerjee S, Stafford LJ, Xia CX, Liu M, and Aggarwal BB.
ONCOGENE 2002, 21: 8852

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Prostate cancer and Curcumin: add spice to your life

Aggarwal BB.
Cancer Biology & Therapy 2008, 7(9):1436-40

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Incidence and mortality due to prostate cancer around the World

(Parkins DM, 2002)

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Modulation of multiple molecular targets by Curcumin relevant to prostate cancer

Aggarwal BB. Prostate cancer and curcumin: add spice to your life. Cancer Biol Ther. 2008 Sep;7(9):1436-40

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Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines

Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, Pantazis P, Aggarwal BB.
Oncogene 2001, 20 (52):7597-609

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Curcumin suppresses NF-κB, pSTAT3 and COX2 in prostate cancer in vivo

Shishodia, Dorai and Aggarwal (unpublished)

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Curcumin Inhibits the Proliferation of Human Pancreatic Cells

Nuclear Factor-κB and IκB Kinase are Constitutively Active in Human Pancreatic Cells and their Down-regulation by Curcumin is Associated with Suppression of Proliferation and Induction of Apoptosis

Lan Li, Bharat B. Aggarwal, Shishir Shishodia, James Abbruzzese and Razelle Kurzrock
Cancer 101:2351-62

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Phase II trial of curcumin in patients with advanced pancreatic cancer

Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R.
Clinical Cancer Research 2008, 14(14):4491-9

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Curcumin Inhibits Growth of Human Pancreatic Cancer in Mice

Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Li L, Braiteh FS, Kurzrock R. Cancer. 2005 Sep 15;104(6):1322-31

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Liposome-encapsulated Curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis

Li L, Braiteh FS, Kurzrock R.
Cancer, 2005,104(6):1322-31

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Curcumin potentiates antitumor activity of Gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of NF-κB-regulated gene products

Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB.
Cancer Research 2007, 67(8):3853-61

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Curcumin potentiates the effect of Gemzar against pancreatic cancer in orthotopic mouse model

Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclea factor-kappaB-regulated gene products. Cancer Res. 2007 Apr 15;67(8):3853-61

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Curcumin potentiates the effect of Gemzar against pancreatic cancer in orthotopic mouse model

N. Dhillon, B. B. Aggarwal, R. A. Wolff, J. L. Abbruzzese, D. S. Hong, L. H. Camacho, L. Li, F. S.Braiteh, R. Kurzrock

• The only FDA-approved therapies- gemcitabine and erlotinib- produce objective responses in less than 10% of patients.
• The objectives of this trial were to evaluate the toxicity and activity of curcumin, as well as its impact on survival and biologic correlates.
• Patients were treated with 8 grams of curcumin (Sabinsa Corp.) daily by mouth for two months and evaluated radiographically using the RECIST criteria.
• Maintenance therapy was continued at the same dose and schedule until disease progression.
• RESULTS: Seventeen patients were enrolled as of the date of analysis.
• Six were inevaluable: noncompliance (n=1), never dosed (n= 1), noted to have gastric obstruction after one dose (n=1), and too early (n=3).
• Eleven patients were evaluable for response and 15 were evaluable for toxicity.
• To date, four patients have stable disease (2+, 2+, 3+ and 7 months) and one patient had a brief partial remission (73% reduction in tumor size by RECIST) that lasted one month.
• No toxicity was observed. Serum was available for evaluation of pre-and post-dose cytokine levels in thirteen patients. Interestingly, the patient with the partial remission had marked increases in (4-35 fold) in serum IL-1 receptor antagonist, IL-6, IL-10 and IL-8 levels. One to three other patients also had post-treatment increases one or more of the above cytokines, albeit to a lesser extent (2-6 folds).

CONCLUSIONS: We conclude that curcumin is well tolerated and our preliminary results suggest biologic activity in pancreatic cancer.

From ASCO-2006

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A Gift of Time

"If you want to do something, do it now. Don't wait." This advice come from a patient with end-stage pancreatic cancer who was given an unexpected gift of time, thanks to curcumin, the main ingredient in the spice tumeric. When Duane Jacobson first came to the Clinical Center for Targeted Therapy (CCTT) at M. D. Anderson, he had less than three months to live, estimated his oncologist Razelle Kurzrock, M.D., principal investigator of the curcumin trial and also chair of the Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program). More than two years later, he is traveling around the world with his wife Hildrud while enrolled in an NIH-sponsored, phase II clinical trial of curcumin in advanced pancreatic cancer.

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Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of NF-κB signaling

S. Aggarwal, Y. Takada, S. Singh, J. Myers and B. B. Aggarwal
International Journal of Cancer 111, 679-692, 2004

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Targeting constitutive and interleukin-6-inducible STAT 3 pathway in head and neck squamous cell carcinoma cells by Curcumin

Chakravarti N, Myers JN, Aggarwal BB.
International Journal of Cancer 2006;119(6):1268-75

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Curcumin potentiates the apoptosis induced by 5-Fluorouracil in esophageal squamous cell carcinoma (SEG1)

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Curcumin down regulates smokeless tobacco-induced NF-κB activation and COX-2 expression in human oral premalignant and cancer cells

Sharma C, Kaur J, Shishodia S, Aggarwal BB, Ralhan R.
Toxicology 2006, 228(1):1-15

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Curcumin Downregulates Cigarette Smoke-Induced NF-κB Activation Through Inhibition of IκBα Kinase in Human Lung Epithelial Cells: Correlation with Suppression of COX-2, MMP-9 and Cyclin D1

S. Shishodia, P. Potdar, C. G. Gairola and B. B. Aggarwal
Carcinogenesis 2003, 24:1269-1279

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Chemosensitization and radiosensitization of tumors by plant polyphenols

Garg AK, Buchholz TA, Aggarwal BB.
Antioxid Redox Signal, 2005;7(11-12):1630-47

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Curcumin as a chemosensitizer

Rationale for a combination therapy of cancer

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Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of NF-κB and NF-κB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells

Kamat AM, Sethi G, Aggarwal BB.
Molecular Cancer Therapeutics 2007, 6(3):1022-30

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Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nf-κB and nf-κB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells.

Kamat AM, Sethi G, Aggarwal BB.
Molecular Cancer Therapy 2007, 6(3):1022-30.

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Curcumin potentiates the effect of taxol and gemcitabine in bladder cancer

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Curcumin And Colorectal Cancer: Add Spice to Your Life

Ajaikumar B. Kunnumakkara, Sushovan Guha and Bharat B. Aggarwal
Current Colorectal Cancer Reports, 2009, 5: 5-14

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Curcumin potentiates the effect of oxaliplatin against colon cancer in mouse xenograft model

Colo205; mouse; S.C. xenograft; N=5		LoVo; mouse; S.C. xenograft; N=5
Days after innoculation		Days after innoculation

Li L, Ahmed B, Mehta K, Kurzrock R. Liposomal curcumin with and without oxaliplatin: effects on cell growth, optosis, and angiogenesis in colorectal cancer. Mol Cancer Ther. 2007 Apr;6(4):1276-82

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Curcumin inhibits constitutive nf-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma.

Shishodia S, Amin HM, Lai R, Aggarwal BB.
Biochemical Pharmacology 2005, 70(5):700-13

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Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IκB kinase and nf-κB activity and are independent of the B-Raf/MAPK pathway and the Akt pathway

Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R.
Cancer, 2005, 104(4):879-90

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Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nf-κB pathway

Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN, Kamat AA, Spannuth WA, Gershenson DM, Lutgendorf SK, Aggarwal BB, Sood AK.
Clinical Cancer Research 2007, 13(11):3423-30

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Curcumin inhibits the growth of docetaxel-sensitive and resistant ovarian tumors in orthotopic mouse model

Curcumin ( sesamine oil) at 500 mg/kg (42 mg/kg in man) oral gavage.

Lin et al; CCR, 2007

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Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways

Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y.
Molecular Pharmacology 2007, 72(1):29-39

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Curcumin Suppresses the Growth of Malignant Gliomas

Nude mice (N=5) were inoculated subcutaneously with one million U87-MG cells. When tumors reached 50–70 mm3 in volume, intratumoral injections of curcumin (100 mg/kg in DMSO) or vehicle (DMSO) were administered every 24 hours for 7 days. Tumor growth was observed until 16 days after the initiation of treatment. On day 16, tumor growth was inhibited significantly in tumors treated with curcumin compared with the control-treated tumors (3.5 + 2.8 fold vs. 12.5 + 5.9 fold; P < 0.05)

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Curcumin as a radio-sensitizer

Curcumin inhibits γ-radiation-induced NF-κB activation in colon cancer HCT116 cells

Kumar et al (unpublished)

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Curcumin sensitizes HNSCC to γ-radiation

Chao C et al (unpublished)

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Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nf-κB-regulated gene products

Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, Krishnan S.
Clin Cancer Res. 2008 Apr 1;14(7):2128-36.

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Radiosensitization of tumors by curcumin

Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, Krishnan S. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008 Apr 1;14(7):2128-36

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Curcumin suppresses the paclitaxel-induced nf-κB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice.

Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, Price JE.
Clinical Cancer Research
2005 Oct 15;11(20):7490-8

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Curcumin potentiates the effect of paclitaxel by suppressing the metastasis of the human breast cancer to the lung in mouse xenograft model

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Curcumin Inhibits RANKL-Induced NF-κB Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis

A.C. Bharti, Y. Takada, and B. B. Aggarwal
Journal of Immunology,
172: 5940-5947, 2004

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Curcumin Decreases Osteolytic Bone Lesions Induced by Breast Cancer Metastasis

4-to 5-week-old, female BALB/c, nu/nu mice were divided into 3 groups. MDA-MB-231 cells were injected into the left heart ventricle of mice on day 0. Daily treatment with curcumin ( in corn oil, administered as a 100µl suspension by oral gavage) were started immediately and continued until sacrifice on day 28 post-tumor cell inoculation. The number and area of the lesions were quantitatively analyzed using Meta Morph imaging software.

Oyajobi et al

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Cancer treatment requires suppression of multiple cell- signaling/survival pathways!

Curcumin: gene profile

• Performed gene expression profiling study to identify novel targets of curcumin action.
• A cDNA array comprised of 12,625 probes was used to compare total RNA extracted from curcumin-treated, and untreated, MDA-1986 cells for differential gene expression.
• Identified 202 up-regulated mRNAs and 505 transcripts decreased 2 fold or more.
• The pro-apoptotic activating transcription factor 3 (ATF3) was induced over 4 fold. Two negative regulators of growth control (antagonizer of myc transcriptional activity, Mad, and p27kip1) were induced 68 and 3 fold respectively.
• Additionally, two dual-activity phosphatases (CL 100 and MKP-5) which inactivate the JNKs showed augmented expression, coinciding with reduced expression of the upstream activators of JNK (MEKK and MKK4).
• Of the repressed genes, the expression of Frizzled-1, (Wnt receptor), was most strongly attenuated (8 fold).
• Growth control genes (K-sam, encoding the KGF receptor and HER3) as well as the E2F-5 transcription factor, which regulates genes controlling cell proliferation also showed down-regulated expression.
• Treatment of MDA-1986 cells, yielded a rapid, dose-dependent increase in ATF3 protein. Moreover, expression of an exogenous ATF3 cDNA synergized with curcumin in inducing apoptosis.
• In conclusion, we have identified several putative, novel biological targets of curcumin and demonstrated that one (ATF3) contributes to the pro-apoptotic effects of this compound.

Yan C, Jamaluddin MS, Aggarwal B, Myers J, Boyd DD. Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41

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Although curcumin mimics avastin, remicade, enabrel, humira, iressa,herceptin, and celebrex; it has none of the toxicities known to be associated with these drugs

Curcumin-fed rats

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Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases

Aggarwal BB, Harikumar KB.
International Journal of Biochemistry & Cell Biology,
2009, 41(1):40-59

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Add spice to your life

Production data from 2000 faostat.fao.org, (http://www.foodmarketexchange.com/datacenter/product/herb/herb/detail/dc_pi_hs_herb0406.htm). Cancer data from the World Health Organization GLOBOCAN 2002, which approximates cancer rates from around 2000. Crude rate per 100,000 males or females.

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Potential of spice-derived phytochemicals for cancer prevention

Aggarwal BB, Kunnumakkara AB, Harikumar KB, Tharakan ST, Sung B, Anand P.
Planta Medica
2008, 74(13):1560-9

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Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin

Yan C, Jamaluddin MS, Aggarwal B, Myers J, Boyd DD.
Mol Cancer Therapeutics
2005, 4(2):233-41

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Suppression of the nf-κB activation pathway by spice-derived phytochemicals: reasoning for seasoning

Aggarwal BB, Shishodia S.
Annals of New Yark Academy of Sciences
2004, 1030:434-41

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Nonsteroidal anti-inflammatory agents differ in their ability to suppress nf-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation.

Takada Y, Bhardwaj A, Potdar P, Aggarwal BB.
Oncogene
2004, 23(57):9247-58

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Role of chemopreventive agents in cancer therapy

Dorai T, Aggarwal BB.
Cancer Letters
2004, 215(2):129-40

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nf-κB and IκB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis

Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R.
Cancer
2004, 101(10):2351-62

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From chemoprevention to chemotherapy: common targets and common goals

Aggarwal BB, Takada Y, Oommen OV.
Expert Opinion on Investigational Drugs
2004, 13(10):1327-38

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Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling

Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB.
International Journal of Cancer
2004, 111(5):679-92

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Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis

Bharti AC, Shishodia S, Reuben JM, Weber D, Alexanian R, Raj-Vadhan S, Estrov Z, Talpaz M, Aggarwal BB.
Blood
2004, 103(8):3175-84

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Curcumin (diferuloylmethane) inhibits receptor activator of NF-κB ligand-induced NF-κB activation in osteoclast precursors and suppresses osteoclastogenesis

Bharti AC, Takada Y, Aggarwal BB.
Journal of Immunology
2004, 172(10):5940-7

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Curcumin (diferuloylmethane) inhibits receptor activator of NF-κB ligand-induced NF-κB activation in osteoclast precursors and suppresses osteoclastogenesis

Bharti AC, Takada Y, Aggarwal BB.
Journal of Immunology
2004, 172(10):5940-7

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Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells.

Bharti AC, Donato N, Aggarwal BB.
Journal of Immunology
2003, 171(7):3863-71

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Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-κB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1.

Shishodia S, Potdar P, Gairola CG, Aggarwal BB.
Carcinogenesis
2003, 24(7):1269-79

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Anticancer potential of curcumin: preclinical and clinical studies

Aggarwal BB, Kumar A, Bharti AC.
Anticancer Research
2003, 23(1A):363-98

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Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation

Mukhopadhyay A, Banerjee S, Stafford LJ, Xia C, Liu M, Aggarwal BB.
Oncogene
2002, 21(57):8852-61

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Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaB alpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis

Bharti AC, Donato N, Singh S, Aggarwal BB.
Blood
2003, 101(3):1053-62

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Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl

Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB.
Carcinogenesis
2002, 23(1):143-50

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Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines

Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, Pantazis P, Aggarwal BB.
Oncogene
2001, 20(52):7597-609

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Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation

Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB.
Biochemical Pharmacology
1998, 55(6):775-83

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Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines

Mehta K, Pantazis P, McQueen T, Aggarwal BB.
Anticancer Drugs
1997, 8(5):470-81

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

Singh S, Aggarwal BB.
Journal of Biological Chemistry
1995, 270(42):24995-5000

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Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase

Reddy S, Aggarwal BB.
FEBS Letter
1994, 341(1):19-22