Prevention of metastatic pancreatic cancer growth in vivo by induction of apoptosis with genistein, a naturally occurring isoflavonoid.
BACKGROUND
The critical need for novel therapeutic approaches to pancreatic cancer treatment is clear. Genistein, a naturally occurring isoflavonoid, is active against certain solid malignancies, but its effect on pancreatic cancer is unknown.


OBJECTIVE
To investigate the bioactivity of genistein in experimental pancreatic cancer in vitro and in vivo.


METHODS
The effect of intraperitoneal genistein administration on local tumor growth and metastatic disease was determined in an orthotopic nude mouse model. Apoptosis in tumor specimens was determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) technique. In vitro, the effect of genistein on cell growth was assessed by cell count and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) colorimetric assay. Apoptosis was determined in vitro by DNA laddering and annexin-V. Caspase-3 and nuclear factor-kappaB activity were measured following genistein treatment.


RESULTS
In vivo, genistein significantly improved survival, almost completely inhibited metastasis, and increased apoptosis in an orthotopic model of pancreatic cancer. In vitro genistein treatment resulted in apoptosis in all pancreatic cancer cell lines tested, and this appeared to be mediated by activation of caspase-3.


CONCLUSIONS
These findings suggest that the antimetastatic effect of genistein treatment in vivo is mediated by induction of apoptosis. Genistein may have a therapeutic benefit for patients with pancreatic cancer, in particular after surgery, to prevent recurrence of metastatic disease.
Büchler
Peter
P
Department of Surgery, UCLA School of Medicine, University of California and Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, California 90095-6904, USA.
Gukovskaya
Anna S
AS
Mouria
Michelle
M
Büchler
Manuela C
MC
Büchler
Markus W
MW
Friess
Helmut
H
Pandol
Stephen J
SJ
Reber
Howard A
HA
Hines
Oscar J
OJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019833:Genistein / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D016328:NF-kappa B; D019833:Genistein; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases