Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo.
BACKGROUND
2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) that lacks COX-2-inhibitory function. However, despite its inability to block COX-2 activity, DMC is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that both of these drugs are able to involve targets other than COX-2 to exert their recognized cytotoxic effects. However, the molecular components that are involved in mediating these drugs' apoptosis-stimulatory consequences are incompletely understood.


RESULTS
We present evidence that celecoxib and DMC are able to down-regulate the expression of survivin, an anti-apoptotic protein that is highly expressed in tumor cells and known to confer resistance of such cells to anti-cancer treatments. Suppression of survivin is specific to these two drugs, as other coxibs (valdecoxib, rofecoxib) or traditional NSAIDs (flurbiprofen, indomethacin, sulindac) do not affect survivin expression at similar concentrations. The extent of survivin down-regulation by celecoxib and DMC in different tumor cell lines is somewhat variable, but closely correlates with the degree of drug-induced growth inhibition and apoptosis. When combined with irinotecan, a widely used anticancer drug, celecoxib and DMC greatly enhance the cytotoxic effects of this drug, in keeping with a model that suppression of survivin may be beneficial to sensitize cancer cells to chemotherapy. Remarkably, these effects are not restricted to in vitro conditions, but also take place in tumors from drug-treated animals, where both drugs similarly repress survivin, induce apoptosis, and inhibit tumor growth in vivo.


CONCLUSIONS
In consideration of survivin's recognized role as a custodian of tumor cell survival, our results suggest that celecoxib and DMC might exert their cytotoxic anti-tumor effects at least in part via the down-regulation of survivin - in a manner that does not require the inhibition of cyclooxygenase-2. Because inhibition of COX-2 appears to be negligible, it might be worthwhile to further evaluate DMC's potential as a non-coxib alternative to celecoxib for anti-cancer purposes.
Pyrko
Peter
P
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, USA. pyrko@usc.edu
Soriano
Nathaniel
N
Kardosh
Adel
A
Liu
Yen-Ting
YT
Uddin
Jasim
J
Petasis
Nicos A
NA
Hofman
Florence M
FM
Chen
Ching-Shih
CS
Chen
Thomas C
TC
Schönthal
Axel H
AH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D000068579:Celecoxib; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D000077022:Survivin; D014158:Transcription, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C506698:2,5-dimethylcelecoxib; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D000077022:Survivin; D000077146:Irinotecan; D000068579:Celecoxib; D002166:Camptothecin