Effect of Bortezomib on Human Neuroblastoma Cell Growth, Apoptosis, and Angiogenesis

Brignole, Chiara; Marimpietri, Danilo; Pastorino, Fabio; Nico, Beatrice; Paolo, Daniela Di; Cioni, Michela; Piccardi, Federica; Cilli, Michele; Pezzolo, Annalisa; Corrias, Maria Valeria; Pistoia, Vito; Ribatti, Doménico; Pagnan, Gabriella; Ponzoni, Mirco

doi:10.1093/jnci/djj309

Cited by 126 publications

(136 citation statements)

References 52 publications

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“…To evaluate the efficacy of Dasatinib in vivo, we used a murine orthotopic model because (i) NB cells injected directly in the adrenal gland are embedded in a microenvironment that closely mimics that of the human disease 24 ; and (ii) drug uptake is more similar to that of spontaneous NB, which frequently occurs in the adrenals 1 compared with subcutaneous transplants. HTLA-230 and SY5Y cells were chosen for the in vivo study, since they derive from aggressive NB, and have been successfully used in pseudometastatic and orthotopic models.…”

Section: Discussionmentioning

confidence: 99%

“…Mice were anaesthetized with ketamine (Imalgene 1000, Merial Italia SpA., Milan, Italy) and xylazine (Bayer AG, Leverkusen, Germany), subjected to laparotomy, and injected with HTLA-230 or SY5Y cells (1 3 10 6 cells in 20 ll of medium without serum) into the capsule of the left adrenal gland, as previously described. 24 Treatment started 1 or 7 days after tumour cell injection (day 0). Animals (8-10 each in the Dasatinib or vehicle-only groups) were treated daily by oral gavage either with 30 mg/(kg day) or 60 mg/(kg day) Dasatinib depending on the schedule) or with vehicle (80 mM citric acid, pH 3.1) (control groups).…”

Section: In Vivo Studiesmentioning

confidence: 99%

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Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

Vitali

Mancini

Cesi

et al. 2009

Intl Journal of Cancer

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Stage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second-generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model. Dasatinib inhibited cell viability with an IC 50 in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage-independent growth and, in some instances, induced senescence and apoptosis. In HTLA-230 cells, Dasatinib treatment caused down-regulation of c-Kit and c-Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity. To test the efficacy of Dasatinib in vivo, HTLA-230 and SY5Y cells were orthotopically injected in the adrenal gland of nude mice and drug treatments carried out until day 40. In mice injected with HTLA-230 cells, tumour growth was significantly inhibited at the dose of 30 mg/(kg day) when treatment was started 7 days after injection. In animals injected with SY5Y cells that were exquisitely sensitive in vitro (IC 50 5 92 nM), the antitumour effect of Dasatinib was observed at the dose of 60 mg/(kg day) but only when treatment was started 1 day after injection. However, the anti-tumour effect of Dasatinib in vivo was partial in both orthotopic models, emphasizing the importance of testing candidate new drugs in animal environments closely mimicking the human tumour. ' UICCKey words: neuroblastoma; Dasatinib; orthotopic model Neuroblastoma (NB) is the most common childhood extracranial tumour. 1 NB derives from precursor cells of the sympatoadrenal lineage and it can develop anywhere in the sympathetic system. 1 About 40% of NBs at diagnosis are localized tumours which, in general, respond to chemotherapy and have an outcome that spans from favourable (Stages 1, 2 and 3 with no MYCN amplification) to intermediate/poor (Stages 2 and 3 with MYCN amplification). 2 However, the greatest clinical challenge is represented by Stage 4 in children older than 18 months, which accounts for 50% of NB cases at diagnosis. Stage 4 NB is characterized by metastases to distant sites such as cortical bone, bone marrow, and lymph nodes non-contiguous to the primary tumour. 2 Outcome for these patients is generally very poor, a 5-year survival not exceeding 30%. 1 A striking clinical phenotype of NB is stage 4S (S5 special), which occurs in about 8% of cases. 2 These infants have a small primary tumour with widespread involvement of liver, skin, and/or bone marrow, which spontaneously regress in a substantial number of cases. Outcome of 4S tumours is similar to Stages 1 and 2 unless other unfavourable prognostic markers are present. 3 Beside tumour stage, many clinical and genetic features are utilized in NB to modulate appropriate treatment and accurately define prognosis. Age >18 months 4 and histology 5 are potent indicators of poorer ou...

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Section: Discussionmentioning

confidence: 99%

Section: In Vivo Studiesmentioning

confidence: 99%

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

Vitali

Mancini

Cesi

et al. 2009

Intl Journal of Cancer

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“…In subsequent experiments, HTLA-230 cells were injected in the adrenal gland capsule of nude mice to generate orthotopic tumors recapitulating the natural history of primary human NB [42]. The choice of the HTLA-230 cell model was based on previous studies from our group showing that these MYCN-amplified cells formed metastatic tumors containing TEC-lining EM [8].…”

Section: Identification and Immunophenotypic Characterization Of Oct-mentioning

confidence: 99%

“…In order to investigate the kinetics of development of tumor microvessels lined by human or mouse EC, nude mice were inoculated orthotopically with the TNC + HTLA-230 cells [42] and groups of six mice each were sacrificed at various times. ECs lining EM were detected by staining with anti-mCD34 and anti-hCD31 mAbs [8].…”

Section: Kinetics Of Human and Mouse Em Formation In Orthotopic Tumormentioning

confidence: 99%

“…Female Hsd athymic nude (nude/ nude) mice, 7-8 weeks old, were purchased from Harlan Laboratories (Harlan Italy, S Pietro al Natisone, Italy) and housed in sterile enclosures under specific pathogen-free conditions. In all experiments, mice were anesthetized with ketamine (Imalgene 1000, Merial Italia SpA., Milan, Italy), subjected to laparotomy and injected with HTLA-230 or GI-LI-N cells (1.5 × 10 6 cells in 20 µl of saline solution) in the capsule of the left adrenal gland, as previously described [42]. No mice died as a result of this treatment.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

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Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells

Pezzolo¹,

Parodi²,

Marimpietri³

et al. 2011

Cell Res

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Neuroblastoma

Vaidya¹,

Pearson²

2010

Pediatric Hematology and Oncology

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Effect of Bortezomib on Human Neuroblastoma Cell Growth, Apoptosis, and Angiogenesis

Abstract: Bortezomib is an effective inhibitor of neuroblastoma cell growth and angiogenesis. These findings provide the rationale for further clinical investigation of bortezomib in pediatric neuroblastoma.

Cited by 126 publications

References 52 publications

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells

Neuroblastoma

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