Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death

Marta M. Alonso, Hong Jiang, Tomohisa Yokoyama, Jing Xu, Nebiyou B. Bekele, Frederick F Lang Jr, Seiji Kondo, Candelaria Gomez-Manzano, Juan Fueyo-Margareto

Research output: Contribution to journalArticle

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Abstract

Novel therapies are clearly needed for the treatment of gliomas, and strategies that involve combining oncolytic vectors with chemotherapy hold out significant hope for a more effective treatment of this malignancy. Whether chemotherapy acts directly on tumor cells by inducing cell arrest or cell death, or indirectly by blocking tumor angiogenesis, the resulting delay in tumor growth may provide the oncolytic virus with a wider window of opportunity to overcome the challenge imposed by the growth kinetics of the tumor. In this study we sought to determine whether the oncolytic adenovirus Delta-24-RGD, in combination with everolimus (RAD001), would result in an enhanced anti-glioma effect in vivo. Viability assays showed that Delta-24-RGD antitumoral activity is synergistically enhanced by combination with RAD001. Interestingly, combination treatment of Delta-24-RGD with RAD001 induced autophagy in vitro. We showed that Delta-24-RGD improved survival of tumor-bearing animals in a dose-dependent manner. A significant finding was that RAD001 enhanced the anti-glioma effect of Delta-24-RGD and resulted in the long-term survival of 80% of the experimental animals. Immunostaining of the treated tumors showed upregulation of Atg5, thereby indicating the therapeutic induction of autophagy. This is the first report showing that Delta-24-RGD plus RAD001 causes autophagic cell death, and dramatically increases long-term survival rates of glioma-bearing animals.

Original languageEnglish (US)
Pages (from-to)487-493
Number of pages7
JournalMolecular Therapy
Volume16
Issue number3
DOIs
StatePublished - Jan 1 2008

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Autophagy
Glioma
Neoplasms
Oncolytic Viruses
Therapeutics
Drug Therapy
Growth
Everolimus
Adenoviridae
Cell Death
Up-Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. / Alonso, Marta M.; Jiang, Hong; Yokoyama, Tomohisa; Xu, Jing; Bekele, Nebiyou B.; Lang Jr, Frederick F; Kondo, Seiji; Gomez-Manzano, Candelaria; Fueyo-Margareto, Juan.

In: Molecular Therapy, Vol. 16, No. 3, 01.01.2008, p. 487-493.

Research output: Contribution to journalArticle

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