期刊
CANCER LETTERS
卷 329, 期 1, 页码 45-58出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2012.09.020
关键词
Acute myeloid leukemia; Bone marrow microenvironment; Hypoxia; GDC-0941; Sorafenib
类别
资金
- Ministry of Education, Science, Sports and Culture of Japan
- Juntendo Institutional Research Grant of Environmental and Gender Specific Medicine
- Juntendo Institutional Project Research Program
- Leukemia and Lymphoma Society
- DRP, Leukemia Spore [5 P50 CA100632-08, 5P01 CA55164-17]
- [1R01CA155056-01]
- [CDP-01]
- Grants-in-Aid for Scientific Research [23590689, 24501306] Funding Source: KAKEN
We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches. (c) 2012 Elsevier Ireland Ltd. All rights reserved.
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