Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells.

Abstract

Overexpression of the tumor suppressor gene melanoma differentiation-associated gene-7 (mda-7) induces apoptosis in many cancer cells, and adenoviral-mediated overexpression of mda-7 downregulates beta-catenin and PI 3-kinase signaling in breast cancer cells. Trastuzumab (Herceptin) improves the efficacy of chemotherapeutics against Her-2/neu-overexpressing breast cancer cells. We sought to evaluate the impact of combination therapy of a recombinant adenovirus vector encoding for human mda-7 (Ad-mda7) and Herceptin on Her-2/neu-overexpressing breast cancer. The MCF-7-Her-18 cell line was subjected to treatment with Ad-mda7 with and without Herceptin. Western blot analysis was performed with antibodies to beta-catenin, Akt, and phosphorylated Akt (p-Akt). The same treatment groups were utilized in a nude mouse model in vivo. Treatment was initiated when the tumors reached 100 mm3 in size. In Western blotting, the combination of Ad-mda7 + Herceptin showed decreased levels of beta-catenin, Akt and p-Akt compared with Ad-mda7 or Herceptin alone (P < .05). The in vivo analysis revealed a marked decrease in tumor size with the Ad-mda7 + Herceptin combination (P < .05). These studies demonstrate the growth inhibitory effect of Ad-mda7 + Herceptin on Her-2/neu-overexpressing breast cancer cells in vitro and in vivo. This combination appears to inhibit the pathways involving beta-catenin and Akt, which play important roles in the growth of breast cancer cells.