GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
Identifieur interne : 000805 ( Main/Curation ); précédent : 000804; suivant : 000806GX15–070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
Auteurs : Sonia Cournoyer ; Anissa Addioui ; Assila Belounis ; Mona Beaunoyer ; Carine Nyalendo ; Roxane Le Gall ; Pierre Teira ; Elie Haddad ; Gilles Vassal [France] ; Hervé Sartelet [France]Source :
- BMC Cancer [ 1471-2407 ] ; 2019.
Abstract
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.
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.
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.
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.
Url:
DOI: 10.1186/s12885-019-6195-y
PubMed: 31664947
PubMed Central: 6819521
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</author>
<author><name sortKey="Addioui, Anissa" sort="Addioui, Anissa" uniqKey="Addioui A" first="Anissa" last="Addioui">Anissa Addioui</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2292 3357</institution-id>
<institution-id institution-id-type="GRID">grid.14848.31</institution-id>
<institution>Department of Pathology and Cellular Biology,</institution>
<institution>Université de Montréal,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Belounis, Assila" sort="Belounis, Assila" uniqKey="Belounis A" first="Assila" last="Belounis">Assila Belounis</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2292 3357</institution-id>
<institution-id institution-id-type="GRID">grid.14848.31</institution-id>
<institution>Department of Pathology and Cellular Biology,</institution>
<institution>Université de Montréal,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Beaunoyer, Mona" sort="Beaunoyer, Mona" uniqKey="Beaunoyer M" first="Mona" last="Beaunoyer">Mona Beaunoyer</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Department of Pediatric Surgery,</institution>
<institution>Sainte-Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Nyalendo, Carine" sort="Nyalendo, Carine" uniqKey="Nyalendo C" first="Carine" last="Nyalendo">Carine Nyalendo</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Le Gall, Roxane" sort="Le Gall, Roxane" uniqKey="Le Gall R" first="Roxane" last="Le Gall">Roxane Le Gall</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Teira, Pierre" sort="Teira, Pierre" uniqKey="Teira P" first="Pierre" last="Teira">Pierre Teira</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Department of Pediatric Hemato-Oncology,</institution>
<institution>Sainte-Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Haddad, Elie" sort="Haddad, Elie" uniqKey="Haddad E" first="Elie" last="Haddad">Elie Haddad</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Vassal, Gilles" sort="Vassal, Gilles" uniqKey="Vassal G" first="Gilles" last="Vassal">Gilles Vassal</name>
<affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2284 9388</institution-id>
<institution-id institution-id-type="GRID">grid.14925.3b</institution-id>
<institution>Department of Pediatric Oncology,</institution>
<institution>Institut Gustave Roussy,</institution>
</institution-wrap>
Villejuif, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Villejuif</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sartelet, Herve" sort="Sartelet, Herve" uniqKey="Sartelet H" first="Hervé" last="Sartelet">Hervé Sartelet</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2173 6322</institution-id>
<institution-id institution-id-type="GRID">grid.411418.9</institution-id>
<institution>Research Center,</institution>
<institution>Sainte Justine University Hospital Center,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2292 3357</institution-id>
<institution-id institution-id-type="GRID">grid.14848.31</institution-id>
<institution>Department of Pathology and Cellular Biology,</institution>
<institution>Université de Montréal,</institution>
</institution-wrap>
Montreal, QC Canada</nlm:aff>
<wicri:noCountry code="subfield">QC Canada</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="GRID">grid.413746.3</institution-id>
<institution>Département d’anatomie et cytologie pathologiques,</institution>
<institution>Institut de Biologie et Pathologie, CHU A Michallon,</institution>
</institution-wrap>
38043 Grenoble cedex 09, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>38043 Grenoble cedex 09</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">BMC Cancer</title>
<idno type="eISSN">1471-2407</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p id="Par1">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.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">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.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">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.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">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.</p>
</sec>
</div>
</front>
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