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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References
Abdollahi A, Lipson KE, Sckell A, Zieher H, Klenke F, Poerschke D, Roth A, Han X, Krix M, Bischof M, Hahnfeldt P, Grone HJ, Debus J, Hlatky L and Huber PE . (2003). Cancer Res., 63, 8890–8898.
Baker C, Solorzano CC and Fidler IJ . (2002). Cancer Res., 62, 1996–2003.
Bayless KJ and Davis GE . (2004). J. Biol. Chem., 279, 11686–11695.
Bergers G, Song S, Meyer-Morse N, Bergsland E and Hanahan D . (2003). J. Clin. Invest., 111, 1287–1295.
Beppu K, Jaboine J, Merchant MS, Mackall CL and Thiele CJ . (2004). J. Natl. Cancer, 96, 46–55.
Bogenmann EA . (1996). Int. J. Cancer, 67, 381–386.
Brodeur GM, Pritchadr J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M and Hedborg F . (1993). J. Clin. Oncol., 11, 1466–1477.
Edgell CJ, McDonald CC and Graham JB . (1983). Proc. Natl. Acad. Sci. USA, 80, 3734–3737.
Eggert A, Ikegaki N, Kwiatkowski J, Ihoo H, Brodeur GM and Himelstein BP . (2000). Clin. Cancer Res., 6, 1900–1908.
Fidler IJ and Ellis LM . (1994). Cell, 79, 185–188.
Folkman J . (1971). N. Engl. J. Med., 285, 1182–1186.
Folkman J . (1996). Eur. J. Cancer, 32A, 2534–2539.
Folkman J, Merler E, Abernathy C and Williams G . (1971). J. Exp. Med., 133, 275–288.
Fukazawa H, Noguchi K, Murakami Y and Uehara Y . (2002). Mol. Cancer Ther., 1, 303–309.
Hanahan D and Folkman J . (1996). Cell, 86, 353–364.
Guba M, Von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW and Geissler EK . (2002). Nature Med., 8, 128–135.
Kaicker S, McCrudden KW, Beck L, New T, Huang J, Frischer JS, Seru A, Kadenhe-Chiweshe A, Yokoi A, Kandel JI and Yamashiro DJ . (2003). Int. J. Oncol., 23, 1651–1655.
Kerbel RS . (2001). J. Clin. Oncol., 19, 45S–51S.
Kerbel RS, Viloria-petit A, Klement G and Rak J . (2000). Eur. J. Cancer, 36, 1248–1257.
Keselman HJ, Othman AR, Wilcox RR and Fradette K . (2004). Psychol. Sci., 15, 47–51.
Klement G, Barnchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P and Kerbel RS . (2000). J. Clin. Invest., 105, R15–R24.
Kueng W, Silber E and Eppenberger U . (1989). Anal. Biochem., 182, 16–19.
Kim ES, Soffer SZ, Huang J, Mc Crudden KW, Yokoi A, Manley CA, Middlesworth W, Kandel JJ and Yamashiro DJ . (2002). J. Pediatr. Surg., 37, 518–522.
Maris JM and Matthay KK . (1999). J. Clin. Oncol., 17, 2264–2279.
Meredith JE and Schwartz MA . (1997). Trends. Cell. Biol., 17, 146–150.
Misawa A, Hosoi H, Rsuchiya K and Sugimoto T . (2003). Int. J. Cancer, 104, 233–237.
Nagabuchi E, Vanderkolk WE, Une Y and Ziegler MM . (1997). J. Pediatr. Surg., 32, 287–293.
Page AM and Hieter P . (1999). Annu. Rev. Biochem., 68, 583–609.
Pastorino F, Brignole C, Marimpietri D, Sapra P, Moase EH, Allen TH and Ponzoni M . (2003). Cancer Res., 63, 86–92.
Phillips P, Steward JK and Kumar S . (1976). Int. J. Cancer, 17, 549–588.
Ponzoni M, Bocca P, Chiesa V, De Censi A, Pistoia V, Raffaghello L, Rozzo C and Montaldo PG . (1995). Cancer Res., 55, 853–861.
Ribatti D, Alessandri G, Vacca A, Iurlaro M and Ponzoni M . (1998). Int. J. Cancer, 77, 449–454.
Ribatti D, Gualandris A, Bastaki M, Vacca A, Iurlaro M, Roncali L and Presta M . (1997). J. Vasc. Res., 34, 455–463.
Ribatti D, Vacca A, Nico B, De Falco G, Montaldo PG and Ponzoni M . (2002). Eu. J. Cancer, 38, 750–757.
Svensson A, Backman U, Jonsson E, Larsson R and Christofferson R . (2002). Pediatr. Res., 51, 607–611.
Tallarida RJ . (2001). J. Pharmacol. Exp. Ther., 298, 865–872.
Tallarida RJ . (2002). Pain, 98, 163–168.
Te Velde EA, Vogten JM, Gebbink MF, van Gorp JM, Voest EE and Borel R . (2002). Br. J. Surg., 89, 1302–1309.
Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Ria R, Pellegrino A and Dammacco F . (1999). Blood, 94, 4143–4155.
Vinals F, Chambard JC and Pouysségur G . (2002). J. Biol. Chem., 274, 26776–26782.
Wassberg E, Pahlman S, Westlin JE and Christofferson R . (1997a). Pediatr. Res., 41, 327–333.
Wassberg E, Hedborg F, Skoldenberg E, Stridsberg M and Christofferson R . (1997b). Am. J. Pathol., 1154, 395–403.
Yokoyama Y, Dhanabal M, Griffioen AW, Sukuhatme VP and Ramakrishnam S . (2000). Cancer Res., 60, 2190–2196.
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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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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DOI: https://doi.org/10.1038/sj.onc.1208829
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