AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer

I. V. Subramanian, S. Devineni, R. Ghebre, G. Ghosh, H. P. Joshi, Y. Jing, A. M. Truskinovsky, Sundaram Ramakrishnan

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Endostatin potentiates the antimitotic effects of paclitaxel (taxol) on endothelial cells (ECs). P125A-endostatin and taxol-treated ECs showed multipolar spindles and nuclear lobulation, leading to mitotic catastrophe and cell death. Induction of nuclear abnormalities was found to be dependent on Β-catenin levels as wnt-mediated overexpression of Β-catenin reversed the changes in nuclear morphology. These results prompted us to investigate whether antiangiogenic gene therapy and paclitaxel chemotherapy can synergistically inhibit angiogenesis and tumor growth. We first determined the effect of combination treatment in a transgenic mouse model of breast cancer. Intramuscular injection of recombinant adeno-associated virus type-2 virus induced sustained expression of P125A-endostatin. In vivo studies showed that combination therapy inhibited mammary cancer growth, delayed the onset of multifocal mammary adenocarcinomas, decreased tumor angiogenesis and increased survival in treated mice. In a second model, female athymic mice were orthotopically transplanted with a metastatic human breast cancer cell line. Antiangiogenic gene therapy in combination with paclitaxel inhibited tumor angiogenesis and lung/lymph-node metastasis in this model. These studies demonstrate cooperation between endostatin gene therapy and chemotherapy to inhibit tumor initiation, growth and metastasis.

Original languageEnglish (US)
Pages (from-to)145-154
Number of pages10
JournalGene Therapy
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Fingerprint

Endoreduplication
Endostatins
Paclitaxel
Endothelial Cells
Breast Neoplasms
Neoplasm Metastasis
Genetic Therapy
Catenins
Neoplasms
Growth
Antimitotic Agents
Therapeutics
Drug Therapy
Dependovirus
Intramuscular Injections
Nude Mice
Transgenic Mice
Adenocarcinoma
Breast
Cell Death

Keywords

  • antiangiogenesis
  • breast cancer
  • chemotherapy
  • orthotopic models
  • prevention model

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer. / Subramanian, I. V.; Devineni, S.; Ghebre, R.; Ghosh, G.; Joshi, H. P.; Jing, Y.; Truskinovsky, A. M.; Ramakrishnan, Sundaram.

In: Gene Therapy, Vol. 18, No. 2, 01.02.2011, p. 145-154.

Research output: Contribution to journalArticle

Subramanian, I. V. ; Devineni, S. ; Ghebre, R. ; Ghosh, G. ; Joshi, H. P. ; Jing, Y. ; Truskinovsky, A. M. ; Ramakrishnan, Sundaram. / AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer. In: Gene Therapy. 2011 ; Vol. 18, No. 2. pp. 145-154.
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