| Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone. | |
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MedLine Citation:
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PMID: 22207485 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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NVP-BKM120 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. This study aimed to evaluate the therapeutic efficacy of BKM120 in multiple myeloma (MM). BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However, BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells, insulin-like growth factor, or interleukin-6 does not affect BKM120-induced tumor cell apoptosis. More importantly, BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, BKM120 shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. Low doses of BKM120 and dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating cyclin D1 and induces caspase-dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of BKM120 and suggest that BKM120 alone or together with other MM chemotherapeutics, particularly dexamethasone, may be a promising treatment for MM. |
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Authors:
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Yuhuan Zheng; Jing Yang; Jianfei Qian; Liang Zhang; Yong Lu; Haiyan Li; Heather Lin; Yongsheng Lan; Zhiqiang Liu; Jin He; Sungyoul Hong; Sheeba Thomas; Jatin Shah; Veera Baladandayuthapani; Larry W Kwak; Qing Yi |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-30 |
Journal Detail:
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Title: Journal of molecular medicine (Berlin, Germany) Volume: - ISSN: 1432-1440 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9504370 Medline TA: J Mol Med (Berl) Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Lymphoma/Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0903, Houston, TX, 77030, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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