PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma.
<h4>Background</h4>Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo.&l...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0114583&type=printable |
| _version_ | 1826586492562046976 |
|---|---|
| author | Georg Karpel-Massler Fresia Pareja Pascaline Aimé Chang Shu Lily Chau Mike-Andrew Westhoff Marc-Eric Halatsch John F Crary Peter Canoll Markus D Siegelin |
| author_facet | Georg Karpel-Massler Fresia Pareja Pascaline Aimé Chang Shu Lily Chau Mike-Andrew Westhoff Marc-Eric Halatsch John F Crary Peter Canoll Markus D Siegelin |
| author_sort | Georg Karpel-Massler |
| collection | DOAJ |
| description | <h4>Background</h4>Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo.<h4>Methods</h4>The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model.<h4>Results</h4>The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone.<h4>Conclusions</h4>PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. |
| first_indexed | 2024-12-20T21:40:37Z |
| format | Article |
| id | doaj.art-c508b0d344c448248eb9c713eee63534 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-14T16:10:24Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c508b0d344c448248eb9c713eee635342025-02-23T05:33:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01912e11458310.1371/journal.pone.0114583PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma.Georg Karpel-MasslerFresia ParejaPascaline AiméChang ShuLily ChauMike-Andrew WesthoffMarc-Eric HalatschJohn F CraryPeter CanollMarkus D Siegelin<h4>Background</h4>Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo.<h4>Methods</h4>The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model.<h4>Results</h4>The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone.<h4>Conclusions</h4>PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0114583&type=printable |
| spellingShingle | Georg Karpel-Massler Fresia Pareja Pascaline Aimé Chang Shu Lily Chau Mike-Andrew Westhoff Marc-Eric Halatsch John F Crary Peter Canoll Markus D Siegelin PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. PLoS ONE |
| title | PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. |
| title_full | PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. |
| title_fullStr | PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. |
| title_full_unstemmed | PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. |
| title_short | PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. |
| title_sort | parp inhibition restores extrinsic apoptotic sensitivity in glioblastoma |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0114583&type=printable |
| work_keys_str_mv | AT georgkarpelmassler parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT fresiapareja parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT pascalineaime parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT changshu parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT lilychau parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT mikeandrewwesthoff parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT marcerichalatsch parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT johnfcrary parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT petercanoll parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma AT markusdsiegelin parpinhibitionrestoresextrinsicapoptoticsensitivityinglioblastoma |