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...
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Nature Portfolio
2018-10-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-018-33784-2 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T17:26:11Z |
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| last_indexed | 2024-12-13T17:26:11Z |
| publishDate | 2018-10-01 |
| publisher | Nature Portfolio |
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| spelling | doaj.art-ba23ac173ed440d99429cc6ecf60572d2022-12-21T23:37:11ZengNature PortfolioScientific Reports2045-23222018-10-018111110.1038/s41598-018-33784-2Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systemsEnyuan Shang0Yiru Zhang1Chang Shu2Chiaki Tsuge Ishida3Elena Bianchetti4Mike-Andrew Westhoff5Georg Karpel-Massler6Markus D. Siegelin7Department of Biological Sciences, Bronx Community College, City University of New York, BronxDepartment of Pathology & Cell Biology, Columbia University Medical Center, New YorkDepartment of Pathology & Cell Biology, Columbia University Medical Center, New YorkDepartment of Pathology & Cell Biology, Columbia University Medical Center, New YorkDepartment of Pathology & Cell Biology, Columbia University Medical Center, New YorkDepartment of Pediatrics and Adolescent Medicine, Ulm University Medical CenterDepartment of Neurosurgery, Ulm University Medical CenterDepartment of Pathology & Cell Biology, Columbia University Medical Center, New YorkAbstract 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.https://doi.org/10.1038/s41598-018-33784-2SelinexorXPO1 InhibitionPatient-derived Xenograft ModelsCultured Glioblastoma CellsGlial Brain Tumors |
| spellingShingle | 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 Scientific Reports Selinexor XPO1 Inhibition Patient-derived Xenograft Models Cultured Glioblastoma Cells Glial Brain Tumors |
| title | 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_short | 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 |
| topic | Selinexor XPO1 Inhibition Patient-derived Xenograft Models Cultured Glioblastoma Cells Glial Brain Tumors |
| url | https://doi.org/10.1038/s41598-018-33784-2 |
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