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.
Department of Surgical Oncology, Division of Medicine, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Tamra
T
McKenzie
Yanna
Y
Liu
Michelle
M
Fanale
Stephen G
SG
Swisher
Sunil
S
Chada
Kelly K
KK
Hunt
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