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. 2005 Aug 19;95(11):901–907. doi: 10.1111/j.1349-7006.2004.tb02200.x

Non‐steroidal anti‐inflammatory drugs inhibit cellular proliferation and upregulate cyclooxygenase‐2 protein expression in endometrial cancer cells

Jingchun Gao 1, Kenji Niwa 1,✉, Wenshu Sun 1, Masao Takemura 2, Zenglin Lian 1, Kyoko Onogi 1, Mitsuru Seishima 2, Hideki Mori 3, Teruhiko Tamaya 1
PMCID: PMC11159916  PMID: 15546508

Abstract

We determined the effects of several non‐steroidal anti‐inflammatory drugs (NSAIDs), aspirin (acetylsalicylic acid, ASA), indomethacin and a cyclooxygenase‐2 (COX‐2)‐selective inhibitor (NS398), on cellular proliferation and regulation of COX‐2 protein expression in endometrial cancer cells in vitro, and investigated their modes of action. All three NSAIDs markedly inhibited the proliferation of Ishikawa, HEC‐1A and AN3CA endometrial cancer cell lines in a time‐ and concentration‐dependent manner. ASA and indomethacin triggered apoptosis in cells of all three lines through release of cytosolic cytochrome c, activation of caspase‐9 and ‐3, and cleavage of poly(ADP‐ribose) polymerase (PARP), but NS398 induced minimal apoptosis only in Ishikawa cells. ASA altered the cell cycle distribution, with G2/M phase accumulation of cells, and induced overexpression of Ki‐67 protein. Both ASA and indomethacin reduced the protein levels of Bcl‐2 and Bcl‐xl, but upregulated those of Bax and Bcl‐xs. COX‐2 protein expression and PGE2 production were upregulated by ASA and indomethacin in all three cell lines. However, NS398 did not alter COX‐2 protein expression or PGE2 production in these cells. These results indicate that NSAIDs inhibit proliferation of endometrial cancer cells independently of the reduction of COX‐2 protein expression. A cytochrome c‐dependent apoptotic pathway and/or cell cycle arrest may contribute to the inhibitory effects of these NSAIDs.

Abbreviations:

NSAIDs

non‐steroidal anti‐inflammatory drugs

ASA

acetylsalicylic acid

COX

cyclooxygenase

MTT

[3‐(4,5)‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetra‐zolium bromide

PARP

poly(ADP‐ribose) polymerase

PGE2

prostaglandin E2

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