Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma
Increased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523317300554 |
| _version_ | 1828875059712753664 |
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| author | Barbara Muz Feda Azab Pilar de la Puente Yosef Landesman Abdel Kareem Azab |
| author_facet | Barbara Muz Feda Azab Pilar de la Puente Yosef Landesman Abdel Kareem Azab |
| author_sort | Barbara Muz |
| collection | DOAJ |
| description | Increased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib; hence, it is a promising target in MM patients. Hypoxia is known to mediate tumor progression and drug resistance (including bortezomib resistance) in MM cells. In this study, we tested the effects of selinexor alone or in combination with bortezomib in normoxia and hypoxia on MM cell survival and apoptosis in vitro and in vivo. In vitro, selinexor alone decreased survival and increased apoptosis, resensitizing MM cells to bortezomib. In vivo, we examined the effects of selinexor alone on tumor initiation and tumor progression, as well as selinexor in combination with bortezomib, on tumor growth in a bortezomib-resistant MM xenograft mouse model. Selinexor, used as a single agent, delayed tumor initiation and tumor progression, prolonging mice survival. In bortezomib-resistant xenografts, selinexor overcame drug resistance, significantly decreasing tumor burden and extending mice survival when combined with bortezomib. |
| first_indexed | 2024-12-13T07:50:39Z |
| format | Article |
| id | doaj.art-4e079c28ef4e49519e919ab09bab7791 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 1944-7124 |
| language | English |
| last_indexed | 2024-12-13T07:50:39Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-4e079c28ef4e49519e919ab09bab77912022-12-21T23:54:41ZengElsevierTranslational Oncology1936-52331944-71242017-08-0110463264010.1016/j.tranon.2017.04.010Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple MyelomaBarbara Muz0Feda Azab1Pilar de la Puente2Yosef Landesman3Abdel Kareem Azab4Department of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USADepartment of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USADepartment of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USAKaryopharm Therapeutics, Newton, MA 02459, USADepartment of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USAIncreased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib; hence, it is a promising target in MM patients. Hypoxia is known to mediate tumor progression and drug resistance (including bortezomib resistance) in MM cells. In this study, we tested the effects of selinexor alone or in combination with bortezomib in normoxia and hypoxia on MM cell survival and apoptosis in vitro and in vivo. In vitro, selinexor alone decreased survival and increased apoptosis, resensitizing MM cells to bortezomib. In vivo, we examined the effects of selinexor alone on tumor initiation and tumor progression, as well as selinexor in combination with bortezomib, on tumor growth in a bortezomib-resistant MM xenograft mouse model. Selinexor, used as a single agent, delayed tumor initiation and tumor progression, prolonging mice survival. In bortezomib-resistant xenografts, selinexor overcame drug resistance, significantly decreasing tumor burden and extending mice survival when combined with bortezomib.http://www.sciencedirect.com/science/article/pii/S1936523317300554 |
| spellingShingle | Barbara Muz Feda Azab Pilar de la Puente Yosef Landesman Abdel Kareem Azab Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma Translational Oncology |
| title | Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma |
| title_full | Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma |
| title_fullStr | Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma |
| title_full_unstemmed | Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma |
| title_short | Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma |
| title_sort | selinexor overcomes hypoxia induced drug resistance in multiple myeloma |
| url | http://www.sciencedirect.com/science/article/pii/S1936523317300554 |
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