Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms.
OBJECTIVE
Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of some epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferators activated receptor gamma (PPARgamma) the mechanism by which TZD exert their anticancer effect is currently unclear. Furthermore, the effect of TZD on local motility and metastatic potential of cancer cells is unknown. The authors analysed the effects of two TZD, rosiglitazone and pioglitazone, on invasiveness of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.


METHODS
Expression of PPARgamma in human pancreatic adenocarcinomas and pancreatic carcinoma cell lines was measured by reverse transcription polymerase chain reaction and confirmed by western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Invasion assay was performed in modified Boyden chambers. Gelatinolytic and fibrinolytic activity were evaluated by gel zymography.


RESULTS
TZD inhibited pancreatic cancer cells' invasiveness, affecting gelatinolytic and fibrinolytic activity with a mechanism independent of PPARgamma activation and involving MMP-2 and PAI-1 expression.


CONCLUSIONS
TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth and invasiveness suggesting that these drugs may have application for prevention and treatment of pancreatic cancer in humans.
Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Morgani 85, 50134 Florence, Italy. a.galli@dfc.unifi.it.
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Galli
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Ceni
D W
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Crabb
T
T
Mello
R
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Salzano
C
C
Grappone
S
S
Milani
E
E
Surrenti
C
C
Surrenti
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Casini
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D000077205:Pioglitazone; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D047495:PPAR gamma; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010960:Plasminogen Activators; D020782:Matrix Metalloproteinases; D000077205:Pioglitazone