Cargando…

GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma

BACKGROUND: Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our stud...

Descripción completa

Detalles Bibliográficos
Autores principales: Cournoyer, Sonia, Addioui, Anissa, Belounis, Assila, Beaunoyer, Mona, Nyalendo, Carine, Le Gall, Roxane, Teira, Pierre, Haddad, Elie, Vassal, Gilles, Sartelet, Hervé
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819521/
https://www.ncbi.nlm.nih.gov/pubmed/31664947
http://dx.doi.org/10.1186/s12885-019-6195-y
_version_ 1783463750597083136
author Cournoyer, Sonia
Addioui, Anissa
Belounis, Assila
Beaunoyer, Mona
Nyalendo, Carine
Le Gall, Roxane
Teira, Pierre
Haddad, Elie
Vassal, Gilles
Sartelet, Hervé
author_facet Cournoyer, Sonia
Addioui, Anissa
Belounis, Assila
Beaunoyer, Mona
Nyalendo, Carine
Le Gall, Roxane
Teira, Pierre
Haddad, Elie
Vassal, Gilles
Sartelet, Hervé
author_sort Cournoyer, Sonia
collection PubMed
description BACKGROUND: Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate therapeutic efficiency of GX 15–070, a pan-Bcl-2 family inhibitor, used alone and in combination with conventional drugs or with hydroxychloroquine (HCQ), an autophagy inhibitor. METHODS: Five neuroblastoma cell lines were tested for the cytotoxic activity of GX 15–070 alone or in combination with cisplatin, doxorubicin, HCQ or Z-VAD-FMK a broad-spectrum caspase inhibitor. Apoptosis and autophagy levels were studied by western-blot and FACS. Orthotopic injections were performed on NOD/LtSz-scid/IL-2Rgamma null mice that were treated with either GX 15–070 alone or in combination with HCQ. RESULTS: Synergistic cytotoxicity was observed for the drug combination in all of the 5 neuroblastoma cell lines tested, including MYCN amplified lines and in cancer stem cells. GX 15–070 significantly increased apoptosis and autophagy in neuroblastoma cells as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by HCQ, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agent plays a cytoprotective role. In vivo, GX 15–070 combined with HCQ significantly decreased the growth of the tumor and the number of distant metastases. CONCLUSIONS: Based on the synergistic effect of HCQ and GX 15–070 observed in this study, the combination of these two drugs may be utilized as a new therapeutic approach for neuroblastoma.
format Online
Article
Text
id pubmed-6819521
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-68195212019-10-31 GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma Cournoyer, Sonia Addioui, Anissa Belounis, Assila Beaunoyer, Mona Nyalendo, Carine Le Gall, Roxane Teira, Pierre Haddad, Elie Vassal, Gilles Sartelet, Hervé BMC Cancer Research Article BACKGROUND: Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate therapeutic efficiency of GX 15–070, a pan-Bcl-2 family inhibitor, used alone and in combination with conventional drugs or with hydroxychloroquine (HCQ), an autophagy inhibitor. METHODS: Five neuroblastoma cell lines were tested for the cytotoxic activity of GX 15–070 alone or in combination with cisplatin, doxorubicin, HCQ or Z-VAD-FMK a broad-spectrum caspase inhibitor. Apoptosis and autophagy levels were studied by western-blot and FACS. Orthotopic injections were performed on NOD/LtSz-scid/IL-2Rgamma null mice that were treated with either GX 15–070 alone or in combination with HCQ. RESULTS: Synergistic cytotoxicity was observed for the drug combination in all of the 5 neuroblastoma cell lines tested, including MYCN amplified lines and in cancer stem cells. GX 15–070 significantly increased apoptosis and autophagy in neuroblastoma cells as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by HCQ, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agent plays a cytoprotective role. In vivo, GX 15–070 combined with HCQ significantly decreased the growth of the tumor and the number of distant metastases. CONCLUSIONS: Based on the synergistic effect of HCQ and GX 15–070 observed in this study, the combination of these two drugs may be utilized as a new therapeutic approach for neuroblastoma. BioMed Central 2019-10-29 /pmc/articles/PMC6819521/ /pubmed/31664947 http://dx.doi.org/10.1186/s12885-019-6195-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Cournoyer, Sonia
Addioui, Anissa
Belounis, Assila
Beaunoyer, Mona
Nyalendo, Carine
Le Gall, Roxane
Teira, Pierre
Haddad, Elie
Vassal, Gilles
Sartelet, Hervé
GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
title GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
title_full GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
title_fullStr GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
title_full_unstemmed GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
title_short GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
title_sort gx15–070 (obatoclax), a bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases chemosensitivity in neuroblastoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819521/
https://www.ncbi.nlm.nih.gov/pubmed/31664947
http://dx.doi.org/10.1186/s12885-019-6195-y
work_keys_str_mv AT cournoyersonia gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT addiouianissa gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT belounisassila gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT beaunoyermona gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT nyalendocarine gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT legallroxane gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT teirapierre gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT haddadelie gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT vassalgilles gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma
AT sarteletherve gx15070obatoclaxabcl2familyproteinsinhibitorengendersapoptosisandprosurvivalautophagyandincreaseschemosensitivityinneuroblastoma