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Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Modelстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 12 марта 2014 г.
- Авторы: Kharaziha, Pedram, De Raeve Hendrik, Fristedt Charlotte, Qiao Li, Gruber Astrid, Johnsson, Per, Kokaraki Georgia, Panzar Maria, Laane, Edward, Osterborg Anders, Zhivotovsky Boris, Jernberg-Wiklund, Helena, Grander Dan, Celsing Fredrik, Bjorkholm Magnus, Vanderkerken Karin, Panaretakis Theocharis
- Журнал: Cancer Research
- Том: 72
- Номер: 20
- Год издания: 2012
- Издательство: American Association for Cancer Research
- Местоположение издательства: United States
- Первая страница: 5348
- Последняя страница: 5362
- DOI: 10.1158/0008-5472.CAN-12-0658
- Аннотация: 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. Cancer Res; 72(20); 5348-62. (C) 2012 AACR.
- Добавил в систему: Животовский Борис Давидович