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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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.

• Authors: Tamra McKenzie, Yanna Liu, Michelle Fanale, Stephen G Swisher, Sunil Chada, Kelly K Hunt
• Journal: Surgery (Surgery) Vol. 136 Issue 2 Pg. 437-42 (Aug 2004) ISSN: 0039-6060 [Print] United States
• PMID: 15300212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2004 Elsevier Inc.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CTNNB1 protein, human
• CTNNB1 protein, mouse
• Cytoskeletal Proteins
• Interleukins
• Proto-Oncogene Proteins
• Trans-Activators
• beta Catenin
• interleukin-24
• Receptor, ErbB-2
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Trastuzumab

Topics

• Adenoviridae (genetics)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Apoptosis
• Breast Neoplasms (chemistry, pathology, therapy)
• Cell Line, Tumor
• Cytoskeletal Proteins (analysis)
• Female
• Genes, Tumor Suppressor
• Genetic Therapy
• Humans
• Interleukins (genetics)
• Mice
• Protein Serine-Threonine Kinases (analysis)
• Proto-Oncogene Proteins (analysis)
• Proto-Oncogene Proteins c-akt
• Receptor, ErbB-2 (analysis)
• Trans-Activators (analysis)
• Trastuzumab
• beta Catenin