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Cell cycle inhibition therapy that targets stathmin in in vitro and in vivo models of breast cancer
- Source :
- Cancer gene therapy. 20(5)
- Publication Year :
- 2013
-
Abstract
- Stathmin is the founding member of a family of microtubule-destabilizing proteins that have a critical role in the regulation of mitosis. Stathmin is expressed at high levels in breast cancer and its overexpression is linked to disease progression. Although there is a large body of evidence to support a role for stathmin in breast cancer progression, the validity of stathmin as a viable therapeutic target for breast cancer has not been investigated. Here, we used a bicistronic adenoviral vector that co-expresses green fluorescent protein and a ribozyme that targets stathmin messenger RNA in preclinical breast cancer models with different estrogen receptor (ER) status. We examined the effects of anti-stathmin ribozyme on the malignant phenotype of breast cancer cells in vitro and in xenograft models in vivo both as a single agent and in combination with chemotherapeutic agents. Adenovirus-mediated gene transfer of anti-stathmin ribozyme resulted in a dose-dependent inhibition of proliferation and clonogenicity associated with a G2/M arrest and increase in apoptosis in both ER-positive and ER-negative breast cancer cell lines. This inhibition was markedly enhanced when stathmin-inhibited breast cancer cells were exposed to low concentrations of taxol, which resulted in virtually complete loss of the malignant phenotype. Interestingly, breast cancer xenografts treated with low doses of anti-stathmin therapy and taxol showed regression in a majority of tumors, while some tumors stopped growing completely. In contrast, combination of anti-stathmin ribozyme and adriamycin resulted in only a modest inhibition of growth in vitro and in breast cancer xenografts in vivo. Although inhibition of tumor growth was observed in both the combination treatment groups compared with groups treated with single agent alone, combination of anti-stathmin therapy and taxol had a more profound inhibition of tumorigenicity, as both agents target the microtubule pathway. Clinically, these findings are highly relevant because taxol is one of the most active chemotherapeutic agents in breast cancer. These studies provide the proof-of-principle that stathmin provides an attractive molecular target, which could serve as a primary focus of novel approaches to breast cancer.
- Subjects :
- Cancer Research
Genetic Vectors
Green Fluorescent Proteins
Estrogen receptor
Mice, Nude
Stathmin
Breast Neoplasms
macromolecular substances
Biology
Viral vector
Adenoviridae
Mice
Breast cancer
In vivo
Cell Line, Tumor
medicine
Animals
Humans
RNA, Catalytic
Molecular Biology
Ribozyme
Cell Cycle Checkpoints
Genetic Therapy
medicine.disease
Molecular biology
Combined Modality Therapy
Xenograft Model Antitumor Assays
In vitro
Apoptosis
Doxorubicin
biology.protein
Cancer research
Molecular Medicine
Female
Subjects
Details
- ISSN :
- 14765500
- Volume :
- 20
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cancer gene therapy
- Accession number :
- edsair.doi.dedup.....8d70196aef7e682f226a4c64354d9789