Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems

Abstract XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is cri...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Enyuan Shang, Yiru Zhang, Chang Shu, Chiaki Tsuge Ishida, Elena Bianchetti, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Selinexor XPO1 Inhibition Patient-derived Xenograft Models Cultured Glioblastoma Cells Glial Brain Tumors Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ba23ac173ed440d99429cc6ecf60572d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ba23ac173ed440d99429cc6ecf60572d
record_format	dspace
spelling	oai:doaj.org-article:ba23ac173ed440d99429cc6ecf60572d2021-12-02T15:09:03ZDual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems10.1038/s41598-018-33784-22045-2322https://doaj.org/article/ba23ac173ed440d99429cc6ecf60572d2018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33784-2https://doaj.org/toc/2045-2322Abstract XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors.Enyuan ShangYiru ZhangChang ShuChiaki Tsuge IshidaElena BianchettiMike-Andrew WesthoffGeorg Karpel-MasslerMarkus D. SiegelinNature PortfolioarticleSelinexorXPO1 InhibitionPatient-derived Xenograft ModelsCultured Glioblastoma CellsGlial Brain TumorsMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Selinexor XPO1 Inhibition Patient-derived Xenograft Models Cultured Glioblastoma Cells Glial Brain Tumors Medicine R Science Q
spellingShingle	Selinexor XPO1 Inhibition Patient-derived Xenograft Models Cultured Glioblastoma Cells Glial Brain Tumors Medicine R Science Q Enyuan Shang Yiru Zhang Chang Shu Chiaki Tsuge Ishida Elena Bianchetti Mike-Andrew Westhoff Georg Karpel-Massler Markus D. Siegelin Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
description	Abstract XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors.
format	article
author	Enyuan Shang Yiru Zhang Chang Shu Chiaki Tsuge Ishida Elena Bianchetti Mike-Andrew Westhoff Georg Karpel-Massler Markus D. Siegelin
author_facet	Enyuan Shang Yiru Zhang Chang Shu Chiaki Tsuge Ishida Elena Bianchetti Mike-Andrew Westhoff Georg Karpel-Massler Markus D. Siegelin
author_sort	Enyuan Shang
title	Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
title_short	Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
title_full	Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
title_fullStr	Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
title_full_unstemmed	Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
title_sort	dual inhibition of bcl-2/bcl-xl and xpo1 is synthetically lethal in glioblastoma model systems
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/ba23ac173ed440d99429cc6ecf60572d
work_keys_str_mv	AT enyuanshang dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT yiruzhang dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT changshu dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT chiakitsugeishida dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT elenabianchetti dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT mikeandrewwesthoff dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT georgkarpelmassler dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems AT markusdsiegelin dualinhibitionofbcl2bclxlandxpo1issyntheticallylethalinglioblastomamodelsystems
_version_	1718387962644791296

Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems

Ejemplares similares