Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway.
OBJECTIVE
Curcumin, a component of turmeric, has been shown to suppress inflammation and angiogenesis largely by inhibiting the transcription factor nuclear factor-kappaB (NF-kappaB). This study evaluates the effects of curcumin on ovarian cancer growth using an orthotopic murine model of ovarian cancer.


METHODS
In vitro and in vivo experiments of curcumin with and without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8-MDR in athymic mice. NF-kappaB modulation was ascertained using electrophoretic mobility shift assay. Evaluation of angiogenic cytokines, cellular proliferation (proliferating cell nuclear antigen), angiogenesis (CD31), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) was done using immunohistochemical analyses.


RESULTS
Curcumin inhibited inducible NF-kappaB activation and suppressed proliferation in vitro. In vivo dose-finding experiments revealed that 500 mg/kg orally was the optimal dose needed to suppress NF-kappaB and signal transducers and activators of transcription 3 activation and decrease angiogenic cytokine expression. In the SKOV3ip1 and HeyA8 in vivo models, curcumin alone resulted in 49% (P = 0.08) and 55% (P = 0.01) reductions in mean tumor growth compared with controls, whereas when combined with docetaxel elicited 96% (P < 0.001) and 77% reductions in mean tumor growth compared with controls. In mice with multidrug-resistant HeyA8-MDR tumors, treatment with curcumin alone and combined with docetaxel resulted in significant 47% and 58% reductions in tumor growth, respectively (P = 0.05). In SKOV3ip1 and HeyA8 tumors, curcumin alone and with docetaxel decreased both proliferation (P < 0.001) and microvessel density (P < 0.001) and increased tumor cell apoptosis (P < 0.05).


CONCLUSIONS
Based on significant efficacy in preclinical models, curcumin-based therapies may be attractive in patients with ovarian carcinoma.
Lin
Yvonne G
YG
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Kunnumakkara
Ajaikumar B
AB
Nair
Asha
A
Merritt
William M
WM
Han
Liz Y
LY
Armaiz-Pena
Guillermo N
GN
Kamat
Aparna A
AA
Spannuth
Whitney A
WA
Gershenson
David M
DM
Lutgendorf
Susan K
SK
Aggarwal
Bharat B
BB
Sood
Anil K
AK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis
D000970:Antineoplastic Agents; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D003474:Curcumin