The combined therapeutic effects of bortezomib and fenretinide on neuroblastoma cells involve endoplasmic reticulum stress response

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Abstract

Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma, Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezo mib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G 2-M and G1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.

Original languageEnglish
Pages (from-to)1199-1209
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number4
DOIs
Publication statusPublished - Feb 15 2009

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Fenretinide
Endoplasmic Reticulum Stress
Therapeutic Uses
Neuroblastoma
Chorioallantoic Membrane
Cell Proliferation
Pharmaceutical Preparations
Apoptosis
G1 Phase Cell Cycle Checkpoints
Proteasome Inhibitors
Trypan Blue
Retinoids
DNA Fragmentation
Chick Embryo
S Phase
Antineoplastic Agents
Thymidine
Transcriptional Activation
Bortezomib
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{65b8efe855ce4c719a8d6631d4c13ffe,
title = "The combined therapeutic effects of bortezomib and fenretinide on neuroblastoma cells involve endoplasmic reticulum stress response",
abstract = "Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma, Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezo mib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G 2-M and G1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.",
author = "Gabriella Pagnan and Paolo, {Daniela Di} and Roberta Carosio and Fabio Pastorino and Danilo Marimpietri and Chiara Brignole and Annalisa Pezzolo and Monica Loi and Galietta, {Luis J V} and Federica Piccardi and Michele Cilli and Beatrice Nico and Domenico Ribatti and Vito Pistoia and Mirco Ponzoni",
year = "2009",
month = "2",
day = "15",
doi = "10.1158/1078-0432.CCR-08-2477",
language = "English",
volume = "15",
pages = "1199--1209",
journal = "Clinical Cancer Research",
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TY - JOUR

T1 - The combined therapeutic effects of bortezomib and fenretinide on neuroblastoma cells involve endoplasmic reticulum stress response

AU - Pagnan, Gabriella

AU - Paolo, Daniela Di

AU - Carosio, Roberta

AU - Pastorino, Fabio

AU - Marimpietri, Danilo

AU - Brignole, Chiara

AU - Pezzolo, Annalisa

AU - Loi, Monica

AU - Galietta, Luis J V

AU - Piccardi, Federica

AU - Cilli, Michele

AU - Nico, Beatrice

AU - Ribatti, Domenico

AU - Pistoia, Vito

AU - Ponzoni, Mirco

PY - 2009/2/15

Y1 - 2009/2/15

N2 - Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma, Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezo mib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G 2-M and G1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.

AB - Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma, Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezo mib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G 2-M and G1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.

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U2 - 10.1158/1078-0432.CCR-08-2477

DO - 10.1158/1078-0432.CCR-08-2477

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JF - Clinical Cancer Research

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