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

Surgery. 2004 Aug;136(2):437-42. doi: 10.1016/j.surg.2004.05.022.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Apoptosis*
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / pathology
  • Breast Neoplasms / 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

Substances

  • 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