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Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin

Oncogene volume 24, pages 6785–6795 (2005)Cite this article

Abstract

The aim of this study was to evaluate the synergistic antiangiogenic effect of low dose of vinblastine (VBL) and rapamycin (RAP) in neuroblastoma (NB). Both in vitro (endothelial cells proliferation assay; TUNEL assay; phosphatidylserine exposure and cell cycle analysis) and in vivo (chick embryo chorioallantoic membrane, CAM) assays were used. Each compound alone was able to induce a significant dose- and time-response inhibition of in vitro endothelial cells (EC) growth. Interaction index evaluation indicates that a synergistic effect was found when both drugs were combined at very low doses. Comparable effects were obtained when EC were preincubated with conditioned medium (CM) derived from the human NB cell line HTLA-230. Morphological changes were induced by each drug, and their combination resulted in a clear and stronger effect. Apoptosis was demonstrated by the TUNEL assay and confirmed by Annexin V-FITC staining of EC treated with VBL, showing an increase in the percentage of cells with a G2–M and sub-G1 DNA content, whereas in those treated with RAP a block in the G1 cell fraction and inhibition of progression to the S phase were observed. Here too, the combination resulted in a synergistic cell cycle arrest and induction of apoptosis. Similar results were obtained in vivo with the CAM assay. The angiogenic responses induced by HTLA-230-derived CM, NB tumor xenografts, and human NB biopsy specimens were inhibited by each drug and more significantly by their combination. The observation that these well-known drugs display synergistic effects as antiangiogenics when administered frequently at very low dose may be of significance in the designing of new ways of treating NB.

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Acknowledgements

We thank F Morandi and A Pezzolo for expert technical assistance, F Pastorino, C Brignole, G Pagnan and V Pistoia for helpful discussions and C Bernardini for editing. This work was supported by the Fondazione Italiana per la lotta al Neuroblastoma, and Fondazione Compagnia di San Paolo, the Associazione Italiana Ricerca Cancro (AIRC).

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Author notes

  1. Mirco Ponzoni and Domenico Ribatti: These authors contributed equally to this work

Authors and Affiliations

  1. Differentiation Therapy Unit Laboratory of Oncology, G Gaslini Childrens' Hospital, Genoa, 16148, Italy

    Danilo Marimpietri & Mirco Ponzoni

  2. Department of Human Anatomy and Histology, University of Bari Medical School, Piazza G. Cesare 11, Policlinico, 70124, Bari, Italy

    Beatrice Nico, Domenica Mangieri & Domenico Ribatti

  3. Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, 70124, Bari, Italy

    Angelo Vacca

  4. Laboratory of Pathophysiology of Uremia, G Gaslini Childrens' Hospital, Genoa, 16148, Italy

    Paolo Catarsi

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  1. Danilo Marimpietri
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Correspondence to Domenico Ribatti.

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Marimpietri, D., Nico, B., Vacca, A. et al. Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin. Oncogene 24, 6785–6795 (2005). https://doi.org/10.1038/sj.onc.1208829

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