Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9

International Journal of Cancer - Tập 113 Số 5 - Trang 803-810 - 2005
Haiming Ding1, Chunhua Han1, Jianhua Zhu2, Ching‐Shih Chen3,2, Steven M. D’Ambrosio3,4,1
1Department of Radiology, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA
2Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA
3Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
4Department of Pharmacology, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

Tóm tắt

AbstractCelecoxib is a potent nonsteroid antiinflammatory drug (NSAID) that has shown great promise in cancer chemoprevention and treatment. The tumor suppression activity of celecoxib and other NSAIDs have been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is a specific inhibitor of cyclooxygenase (COX)‐2, recent data indicate that its apoptotic properties may also be mediated through COX‐independent pathways. In our study, we evaluated second generation celecoxib derivatives, lacking COX‐2 inhibitory activity, in a premalignant and malignant human oral cell culture model to determine their potential anticancer effect and mechanisms responsible for the COX‐independent apoptotic activity. Celecoxib and its derivatives delayed the progression of cells through the G2/M phase and induced apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced apoptosis and cell cycle delay. Apoptosis and cell cycle arrest appeared to be independent of derivative induced inhibition of PDK1 and phosphorylation of Akt and Erk1/2. Derivatives induced apoptosis was mediated by the cleavage and activation of caspase‐9 and caspase‐3, but not caspase 8, implicating the mitochondrial pathway for apoptosis induction. Inhibitors of caspase‐3 and caspase‐9 and cyclosporin A, a mitochondrial membrane potential stabilizer, attenuated derivative induced apoptosis. Inhibition of caspase‐3 prevented the activation of caspase 8, while the inhibition of caspase‐9 inhibitor blocked activation of both caspase 3 and 8 by the derivatives. Apoptosis was independent of Bcl‐2. These results indicate that the second generation celecoxib derivatives induce apoptosis in human oral cancer lines by the disruption of mitochondrial membrane potential activating caspase 9 and downstream caspase 3 and 8. This suggests that the modification of the celecoxib structure can lead to highly effective COX‐independent growth inhibitory and apoptotic agents in chemoprevention and therapy. © 2004 Wiley‐Liss, Inc.

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Tài liệu tham khảo

10.1615/JEnvironPatholToxicolOncol.v21.i2.90

10.1034/j.1600-0714.2003.00054.x

10.1016/S1368-8375(03)00012-5

10.1002/ijc.11499

Williams CS, 2000, Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models, Cancer Res, 60, 6045

10.1038/sj.onc.1206920

Waskewich C, 2002, Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX‐2‐negative hematopoietic and epithelial cell lines, Cancer Res, 62, 2029

10.1093/jnci/94.23.1745

10.1038/sj.onc.1205778

10.1124/mol.62.5.1207

10.1038/sj.neo.7900226

10.1002/ijc.1518

10.1096/fj.01-0390rev

10.1016/S0006-2952(01)00857-7

10.1093/jnci/94.4.252

10.1096/fj.01-0299fje

10.1002/hon.685

10.1016/S0300-9084(02)01368-8

10.1038/sj.cdd.4401160

10.1007/s00280-002-0522-7

10.1016/S0009-8981(02)00297-8

10.1023/A:1016167228059

10.1016/S0300-9084(02)01380-9

10.1074/jbc.M300750200

10.1016/S0006-291X(03)00618-1

10.1096/fj.02-0947fje

10.1002/art.10969

10.1038/sj.onc.1206837

10.1074/jbc.M301744200

10.1074/jbc.275.15.11397

10.1093/jnci/94.8.585

10.1158/0008-5472.CAN-03-4063

10.1158/0008-5472.CAN-03-2396

10.1073/pnas.87.4.1268

10.1016/S0065-2571(00)00015-7

Beauparlant P, 2003, Therapeutic activation of caspases in cancer: a question of selectivity, Curr Opin Drug Discov Devel, 6, 179

10.1016/S0300-483X(02)00464-X

10.1345/aph.1C489

Gumgumji AA, 2003, Role of COX‐2 specific inhibitors in oncogenesis, J Coll Physicians Surg Pak, 13, 361

10.1016/S0014-5793(03)00562-3

10.1074/jbc.M203668200

10.1053/sonc.2002.34057

10.1128/MCB.22.20.7226-7241.2002

10.1038/sj.onc.1205728

10.1007/s00018-002-8465-z

10.1016/S0014-5793(03)01464-9

10.1016/S0006-291X(03)00614-4

10.1038/sj.onc.1203824

10.1038/sj.onc.1206280

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International Journal of Cancer

Tập 113 Số 5

803-810

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