Combination of cyclooxygenase-2 inhibitors and oxaliplatin increases the growth inhibition and death in human colon cancer cells.
The cyclooxygenase-2 (COX-2) protein is highly expressed in a variety of human cancers and has been reported to promote tumor growth. Non-steroidal anti-inflammatory drugs such as etodolac and celecoxib have been shown to inhibit COX-2 activity and may play a role in the chemoprevention of cancer. Oxaliplatin is a third-generation platinum compound that exhibits a different spectrum of activity compared with cisplatin. Other cisplatin-resistant tumors can still respond to oxaliplatin. However, the anticancer ability of the combination of COX-2 inhibitors and oxaliplatin is still unknown. In this study, we investigated the effects of combination of COX-2 inhibitors and oxaliplatin on the cell growth and survival in human colon cancer cells. Treatments with etodolac (0.3-0.5 mM) or celecoxib (20-80 microM) for 24 h concentration-dependently induced the cytotoxicity in the RKO colon carcinoma cells. Etodolac and celecoxib did not alter the COX-2 protein levels but inhibited its enzyme activity to reduce prostaglandin E2 production. Furthermore, the cell survival was concentration-dependently decreased following oxaliplatin (1-100 microM, 24 h) treatment. Combination of oxaliplatin and etodolac additively increased the death and growth inhibition of RKO cells. Survivin, an inhibitor protein of apoptosis, mediates anti-apoptosis and promotes cell division in cancer cells. Oxaliplatin or COX-2 inhibitors significantly decreased the levels of survivin proteins. Moreover, survivin proteins were markedly diminished following co-treatment with oxaliplatin and etodolac. Together, this is the first report that combination of COX-2 inhibitors and oxaliplatin can increase the reduction of survivin protein expression, growth inhibition, and death in human colon cancer cells.
Lin
Johnson
J
Hemato-Oncology Section, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.
Hsiao
Po-Wen
PW
Chiu
Ted H
TH
Chao
Jui-I
JI
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D000077022:Survivin
C107489:BIRC5 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077022:Survivin; D000077150:Oxaliplatin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone