Synergistic tumoricidal effect between celecoxib and adenoviral-mediated delivery of mda-7 in human breast cancer cells.
BACKGROUND
Celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, blocks growth and promotes apoptosis in breast cancer cells. The PI3K/Akt pathway is important in cell survival, and COX-2 and Akt might promote growth via a positive feedback loop. We have shown that adenoviral delivery of mda-7 (Ad-mda7) in breast cancer down-regulates Akt. We hypothesized that combining Ad-mda7 and celecoxib could mediate tumor suppression in COX-2 overexpressing breast cancer cells.


METHODS
Two COX-2 overexpressing human breast cancer cell lines (Her-18 and MDA-MB-436) were treated with celecoxib (20 micromol/L and 50 micromol/L) and Ad-mda7 (multiplicity of infection, 1000 and 2000 viral particles/cell). Adenovirus encoding the luciferase gene was used as a control. We assessed proliferation, cell cycle, apoptosis, prostaglandin E2 production, and changes in protein expression. Statistical analysis was performed by using the Student t test.


RESULTS
Regardless of HER-2/neu status, cell growth was markedly inhibited by celecoxib, Ad-mda7, and the combination compared with controls. Celecoxib + Ad-mda7 showed a greater than additive increase in cell death compared with either monotherapy (P < .05) and resulted in cell cycle block and apoptosis (P < .05). Both cell lines showed decreased prostaglandin E2 production after combination treatment compared with controls (P < .05), with decreased expression of COX-2, Akt, and phosphorylated Akt (P < .05).


CONCLUSIONS
Enhanced antitumor activity is achieved in breast cancer by combining celecoxib and Ad-mda7 regardless of HER-2/neu status. This occurs through inhibition of COX-2 expression and down-regulation of Akt. Combining Ad-mda7 with COX-2 inhibition provides a novel method of treatment in breast cancer.
Suh
Young-Jin
YJ
Department of Surgical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
Chada
Sunil
S
McKenzie
Tamra
T
Liu
Yanna
Y
Swisher
Stephen G
SG
Lucci
Anthony
A
Hunt
Kelly K
KK
D000256:Adenoviridae; D001943:Breast Neoplasms; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity*; D000099180:Interleukin-24
D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007378:Interleukins; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; D000099180:Interleukin-24; C496540:PTGS2 protein, human