Suh Young-Jin, Chada Sunil, McKenzie Tamra, Liu Yanna, Swisher Stephen G, Lucci Anthony, Hunt Kelly K
Department of Surgical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
Surgery. 2005 Sep;138(3):422-30. doi: 10.1016/j.surg.2005.06.032.
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.
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.
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).
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.
塞来昔布是一种选择性环氧化酶2（COX-2）抑制剂，可抑制乳腺癌细胞生长并促进其凋亡。PI3K/Akt信号通路在细胞存活中起重要作用，COX-2和Akt可能通过正反馈回路促进细胞生长。我们已经证明，腺病毒介导的mda-7（Ad-mda7）在乳腺癌中可下调Akt。我们推测，联合使用Ad-mda7和塞来昔布可介导COX-2过表达的乳腺癌细胞的肿瘤抑制作用。
用塞来昔布（20 μmol/L和50 μmol/L）和Ad-mda7（感染复数，1000和2000个病毒颗粒/细胞）处理两种COX-2过表达的人乳腺癌细胞系（Her-18和MDA-MB-436）。编码荧光素酶基因的腺病毒用作对照。我们评估了细胞增殖、细胞周期、凋亡、前列腺素E2的产生以及蛋白表达的变化。采用Student t检验进行统计学分析。
无论HER-2/neu状态如何，与对照组相比，塞来昔布、Ad-mda7及其联合使用均显著抑制细胞生长。与单一疗法相比，塞来昔布+Ad-mda7导致的细胞死亡增加大于两者相加的效果（P <.05），并导致细胞周期阻滞和凋亡（P <.05）。与对照组相比，联合治疗后两种细胞系的前列腺素E2产生均减少（P <.05），COX-2、Akt和磷酸化Akt的表达也降低（P <.05）。
无论HER-2/neu状态如何，联合使用塞来昔布和Ad-mda7均可增强乳腺癌的抗肿瘤活性。这是通过抑制COX-2表达和下调Akt来实现的。将Ad-mda7与COX-2抑制联合使用为乳腺癌提供了一种新的治疗方法。
