Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells
The proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. However, long-term remissions are difficult to achieve, and myeloma cells often develop secondary resistance to proteasome inhibitors. We recently demonstrated that the extraordinary sensitivity of myel...
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| Format: | Article |
| Language: | English |
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Elsevier
2010-07-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558610800296 |
| _version_ | 1818351901665656832 |
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| author | Silke Meister Benjamin Frey Veronika R. Lang Udo S. Gaipl Georg Schett Ursula Schlötzer-Schrehardt Reinhard E. Voll |
| author_facet | Silke Meister Benjamin Frey Veronika R. Lang Udo S. Gaipl Georg Schett Ursula Schlötzer-Schrehardt Reinhard E. Voll |
| author_sort | Silke Meister |
| collection | DOAJ |
| description | The proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. However, long-term remissions are difficult to achieve, and myeloma cells often develop secondary resistance to proteasome inhibitors. We recently demonstrated that the extraordinary sensitivity of myeloma cells toward bortezomib is dependent on their extensive immunoglobulin synthesis, thereby triggering the terminal unfolded protein response (UPR). Here, we investigated whether verapamil, an inhibitor of the multidrug resistance (MDR) gene product, can enhance the cytotoxicity of bortezomib. The combination of bortezomib and verapamil synergistically decreased the viability of myeloma cells by inducing cell death. Importantly, bortezomib-mediated activation of major UPR components was enhanced byverapamil. The combination of bortezomib and verapamil resulted in caspase activation followed by poly(ADP-ribose) polymerase cleavage, whereas nuclear factor κB (NF-κB) activity declined in myeloma cells. Also, we found reduced immunoglobulin G secretion along with increased amounts of ubiquitinylated proteins within insoluble fractions of myeloma cells when using the combination treatment. Verapamil markedly induced reactive oxygen species production and autophagiclike processes. Furthermore, verapamil decreased MDR1 expression. We conclude that verapamil increased the antimyeloma effect of bortezomib by enhancing ER stress signals along with NF-κB inhibition, leading to cell death. Thus, the combination of bortezomib with verapamil may improve the efficacy of proteasome inhibitory therapy. |
| first_indexed | 2024-12-13T18:45:06Z |
| format | Article |
| id | doaj.art-9112c639c3f24f57acdc43a98a19419d |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-13T18:45:06Z |
| publishDate | 2010-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-9112c639c3f24f57acdc43a98a19419d2022-12-21T23:35:06ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022010-07-0112755056110.1593/neo.10228Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma CellsSilke Meister0Benjamin Frey1Veronika R. Lang2Udo S. Gaipl3Georg Schett4Ursula Schlötzer-Schrehardt5Reinhard E. Voll6IZKF N2, Nikolaus-Fiebiger-Center of Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, GermanyDepartment of Radiation Oncology, University of Erlangen-Nuremberg, Erlangen, GermanyIZKF N2, Nikolaus-Fiebiger-Center of Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, GermanyDepartment of Radiation Oncology, University of Erlangen-Nuremberg, Erlangen, GermanyDepartment for Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, GermanyDepartment of Ophthalmology, University of Erlangen-Nuremberg, Erlangen, GermanyIZKF N2, Nikolaus-Fiebiger-Center of Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, GermanyThe proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. However, long-term remissions are difficult to achieve, and myeloma cells often develop secondary resistance to proteasome inhibitors. We recently demonstrated that the extraordinary sensitivity of myeloma cells toward bortezomib is dependent on their extensive immunoglobulin synthesis, thereby triggering the terminal unfolded protein response (UPR). Here, we investigated whether verapamil, an inhibitor of the multidrug resistance (MDR) gene product, can enhance the cytotoxicity of bortezomib. The combination of bortezomib and verapamil synergistically decreased the viability of myeloma cells by inducing cell death. Importantly, bortezomib-mediated activation of major UPR components was enhanced byverapamil. The combination of bortezomib and verapamil resulted in caspase activation followed by poly(ADP-ribose) polymerase cleavage, whereas nuclear factor κB (NF-κB) activity declined in myeloma cells. Also, we found reduced immunoglobulin G secretion along with increased amounts of ubiquitinylated proteins within insoluble fractions of myeloma cells when using the combination treatment. Verapamil markedly induced reactive oxygen species production and autophagiclike processes. Furthermore, verapamil decreased MDR1 expression. We conclude that verapamil increased the antimyeloma effect of bortezomib by enhancing ER stress signals along with NF-κB inhibition, leading to cell death. Thus, the combination of bortezomib with verapamil may improve the efficacy of proteasome inhibitory therapy.http://www.sciencedirect.com/science/article/pii/S1476558610800296 |
| spellingShingle | Silke Meister Benjamin Frey Veronika R. Lang Udo S. Gaipl Georg Schett Ursula Schlötzer-Schrehardt Reinhard E. Voll Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells Neoplasia: An International Journal for Oncology Research |
| title | Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells |
| title_full | Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells |
| title_fullStr | Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells |
| title_full_unstemmed | Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells |
| title_short | Calcium Channel Blocker Verapamil Enhances Reticulum Stress and Death Induced by Proteasome Inhibition in Myeloma Cells |
| title_sort | calcium channel blocker verapamil enhances reticulum stress and death induced by proteasome inhibition in myeloma cells |
| url | http://www.sciencedirect.com/science/article/pii/S1476558610800296 |
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