Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells
Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We al...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/6676 |
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| author | Md. Hafiz Uddin Yiwei Li Husain Yar Khan Irfana Muqbil Amro Aboukameel Rachel E. Sexton Shriya Reddy Yosef Landesman Trinayan Kashyap Asfar S. Azmi Elisabeth I. Heath |
| author_facet | Md. Hafiz Uddin Yiwei Li Husain Yar Khan Irfana Muqbil Amro Aboukameel Rachel E. Sexton Shriya Reddy Yosef Landesman Trinayan Kashyap Asfar S. Azmi Elisabeth I. Heath |
| author_sort | Md. Hafiz Uddin |
| collection | DOAJ |
| description | Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes <i>BAX</i>, <i>T</i><i>P53</i> and <i>CASPASE 9</i>. Mechanistically, KPT-8602-PARPi suppressed <i>AR</i>, <i>ARv7</i>, <i>PSA</i> and AR targets <i>FOXA1</i> and <i>UBE2C</i>. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including <i>BRCA1</i>, <i>BRCA2</i>, <i>CHEK1</i>, <i>EXO1</i>, <i>BLM</i>, <i>RAD51</i>, <i>LIG1</i>, <i>XRCC3</i> and <i>RMI2</i>. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC. |
| first_indexed | 2024-03-10T10:11:07Z |
| format | Article |
| id | doaj.art-d80ce8d44e604aff8ee32b91e68da937 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:11:07Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d80ce8d44e604aff8ee32b91e68da9372023-11-22T01:14:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213667610.3390/ijms22136676Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer CellsMd. Hafiz Uddin0Yiwei Li1Husain Yar Khan2Irfana Muqbil3Amro Aboukameel4Rachel E. Sexton5Shriya Reddy6Yosef Landesman7Trinayan Kashyap8Asfar S. Azmi9Elisabeth I. Heath10Departments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USADepartment of Chemistry, University of Detroit Mercy, Detroit, MI 48221, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USAKaryopharm Therapeutics Inc., Newton, MA 02459, USAKaryopharm Therapeutics Inc., Newton, MA 02459, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USADepartments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USAAberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes <i>BAX</i>, <i>T</i><i>P53</i> and <i>CASPASE 9</i>. Mechanistically, KPT-8602-PARPi suppressed <i>AR</i>, <i>ARv7</i>, <i>PSA</i> and AR targets <i>FOXA1</i> and <i>UBE2C</i>. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including <i>BRCA1</i>, <i>BRCA2</i>, <i>CHEK1</i>, <i>EXO1</i>, <i>BLM</i>, <i>RAD51</i>, <i>LIG1</i>, <i>XRCC3</i> and <i>RMI2</i>. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.https://www.mdpi.com/1422-0067/22/13/6676nuclear exporteltanexorKPT-8602PARP inhibitorscastration resistanceprostate cancer |
| spellingShingle | Md. Hafiz Uddin Yiwei Li Husain Yar Khan Irfana Muqbil Amro Aboukameel Rachel E. Sexton Shriya Reddy Yosef Landesman Trinayan Kashyap Asfar S. Azmi Elisabeth I. Heath Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells International Journal of Molecular Sciences nuclear export eltanexor KPT-8602 PARP inhibitors castration resistance prostate cancer |
| title | Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells |
| title_full | Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells |
| title_fullStr | Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells |
| title_full_unstemmed | Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells |
| title_short | Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells |
| title_sort | nuclear export inhibitor kpt 8602 synergizes with parp inhibitors in escalating apoptosis in castration resistant cancer cells |
| topic | nuclear export eltanexor KPT-8602 PARP inhibitors castration resistance prostate cancer |
| url | https://www.mdpi.com/1422-0067/22/13/6676 |
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