The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice.
Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitroand in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFkappaB, as a consequence of diminished IotakappaB and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFkappa B activity and transcriptional downregulation of AP-1. NFkappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NFkappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFkappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible.
Bachmeier
Beatrice
B
Department of Clinical Chemistry and Clinical Biochemistry, Surgical Hospital, Ludwig-Maximilians-University Munich, Germany. bachmeier@med.uni-muenchen.de
Nerlich
Andreas G
AG
Iancu
Cristina M
CM
Cilli
Michele
M
Schleicher
Erwin
E
Vené
Roberta
R
Dell'Eva
Raffaella
R
Jochum
Marianne
M
Albini
Adriana
A
Pfeffer
Ulrich
U
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D059808:Polyphenols; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D005419:Flavonoids; D051858:Forkhead Transcription Factors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D018808:Transcription Factor AP-1; C090140:Whn protein; D020782:Matrix Metalloproteinases; D003474:Curcumin