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IGF-1 receptor tyro...
IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells.
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- Strömberg, Thomas (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Ekman, Simon (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Girnita, Leonard (author)
- Karolinska Institutet
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- Dimberg, Lina Y (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Larsson, Olle (author)
- Karolinska Institutet
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- Axelson, Magnus (author)
- Karolinska Institutet
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- Lennartsson, Johan (author)
- Ludwiginstitutet för Cancerforskning
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- Hellman, Ulf (author)
- Ludwiginstitutet för Cancerforskning
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- Carlson, Kristina (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Österborg, Anders (author)
- Karolinska Institutet
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Vanderkerken, Karin (author)
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- Nilsson, Kenneth (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Jernberg-Wiklund, Helena (author)
- Uppsala universitet,Institutionen för genetik och patologi
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(creator_code:org_t)
- American Society of Hematology, 2006
- 2006
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 107:2, s. 669-78
- Related links:
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http://www.ncbi.nlm....
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https://urn.kb.se/re...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R beta-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G(2)/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.
Keyword
- Apoptosis/*drug effects
- CDC2 Protein Kinase/metabolism
- Cell Division/*drug effects
- Cell Proliferation/drug effects
- Enzyme Activation
- G2 Phase/*drug effects
- Humans
- Insulin/pharmacology
- Insulin-Like Growth Factor I/pharmacology
- Interleukin-6/pharmacology
- Microtubule-Associated Proteins/metabolism
- Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/metabolism
- Multiple Myeloma/blood supply/*drug therapy/metabolism
- Neoplasm Proteins/metabolism
- Phosphorylation
- Podophyllotoxin/*analogs & derivatives/pharmacology
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Receptor; IGF Type 1/*antagonists & inhibitors/metabolism
- Receptor; Insulin/antagonists & inhibitors/metabolism
- Research Support; Non-U.S. Gov't
- Tumor Cells; Cultured
Publication and Content Type
- ref (subject category)
- art (subject category)
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Blood
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- By the author/editor
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Strömberg, Thoma ...
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Ekman, Simon
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Girnita, Leonard
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Dimberg, Lina Y
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Larsson, Olle
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Axelson, Magnus
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Lennartsson, Joh ...
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Hellman, Ulf
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Carlson, Kristin ...
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Österborg, Ander ...
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Vanderkerken, Ka ...
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Nilsson, Kenneth
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Jernberg-Wiklund ...
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- Articles in the publication
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Blood
- By the university
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Uppsala University
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Karolinska Institutet