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Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model
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- Kharaziha, Pedram (author)
- Karolinska Institutet
- De Raeve, Hendrik (author)
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- Fristedt, Charlotte (author)
- Uppsala universitet,Hematologi och immunologi,jernberg-wiklund
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- Gruber, Astrid (author)
- Panzar, Maria (author)
- Laane, Edward (author)
- Celsing, Fredrik (author)
- Vanderkerken, Karin (author)
- Panaretakis, Theocharis (author)
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- (creator_code:org_t)
- 2012
- 2012
- English.
- In: Cancer Research. - 0008-5472 .- 1538-7445. ; 72:20, s. 5348-5362
- Journal article (peer-reviewed)
Abstract
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- Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, multiple myeloma remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multi-tyrosine kinase inhibitor (TKI), sorafenib, seem a promising treatment approach for multiple myeloma. Here, we show that sorafenib induces cell death in multiple myeloma cell lines and in CD138(+)-enriched primary multiple myeloma patient samples in a caspase-dependent and -independent manner. Furthermore, sorafenib has a strong antitumoral and -angiogenic activity in the 5T33MM mouse model leading to increased overall survival. Multiple myeloma cells undergo autophagy in response to sorafenib, and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in multiple myeloma, is downregulated at the protein level by sorafenib allowing for the execution of cell death, as ectopic overexpression of this protein protects multiple myeloma cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in multiple myeloma cell lines and CD138(+)-enriched primary cells in the presence of bone marrow stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human multiple myeloma, and its efficacy may be potentiated in combination with ABT737.
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