TY - JOUR
T1 - Synergistic tumoricidal effect between celecoxib and adenoviral-mediated delivery of mda-7 in human breast cancer cells
AU - Suh, Young Jin
AU - Chada, Sunil
AU - McKenzie, Tamra
AU - Liu, Yanna
AU - Swisher, Stephen G.
AU - Lucci, Anthony
AU - Hunt, Kelly K.
PY - 2005/9
Y1 - 2005/9
N2 - 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 μmol/L and 50 μmol/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.
AB - 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 μmol/L and 50 μmol/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.
UR - http://www.scopus.com/inward/record.url?scp=26244468059&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=26244468059&partnerID=8YFLogxK
U2 - 10.1016/j.surg.2005.06.032
DO - 10.1016/j.surg.2005.06.032
M3 - Article
C2 - 16213894
AN - SCOPUS:26244468059
SN - 0039-6060
VL - 138
SP - 422
EP - 430
JO - Surgery
JF - Surgery
IS - 3
ER -