Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells.
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.
McKenzie
Tamra
T
Department of Surgical Oncology, Division of Medicine, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Liu
Yanna
Y
Fanale
Michelle
M
Swisher
Stephen G
SG
Chada
Sunil
S
Hunt
Kelly K
KK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000032:analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D015534:Trans-Activators / Q000032:analysis; D000068878:Trastuzumab; D051176:beta Catenin; D000099180:Interleukin-24
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003598:Cytoskeletal Proteins; D007378:Interleukins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D000068878:Trastuzumab; D051176:beta Catenin; D000099180:Interleukin-24; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C494918:AKT1 protein, human