期刊
BLOOD
卷 116, 期 24, 页码 5289-5297出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-02-267963
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资金
- National Basic Research Program of China (973 Program) [NO2009CB918404, NO2010CB912104]
- National Natural Science Foundation of China (NSFC) [30630034, 30870523, 90813034]
- NSFC-joint Foundation of Yunnan Province [U0832602]
- Chinese Academy of Sciences [KSCX2-YW-R-097]
- Science and Technology Commission of Shanghai [08JC1413400, 08431900700]
- Shanghai Ling-Jun Talent Program
All-trans retinoic acid (ATRA), a natural ligand for the retinoic acid receptors (RARs), induces clinical remission in most acute promyelocytic leukemia (APL) patients through the induction of differentiation and/or eradication of leukemia-initiating cells. Here, we identify a novel natural ent-kaurene diterpenoid derived from Isodon pharicus leaves, called pharicin B, that can rapidly stabilize RAR-alpha protein in various acute myeloid leukemic (AML) cell lines and primary leukemic cells from AML patients, even in the presence of ATRA, which is known to induce the loss of RAR-alpha protein. Pharicin B also enhances ATRA-dependent the transcriptional activity of RAR-alpha protein in the promyelocytic leukemia-RAR alpha-positive APL cell line NB4 cells. We also showed that pharicin B presents a synergistic or additive differentiation-enhancing effect when used in combination with ATRA in several AML cell lines and, especially, some primary leukemic cells from APL patients. In addition, pharicin B can overcome retinoid resistance in 2 of 3 NB4-derived ATRA-resistant subclones. These findings provide a good example for chemical biology-based investigations of pathophysiological and therapeutic significances of RAR-alpha and PML-RAR-alpha proteins. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients. (Blood. 2010;116(24):5289-5297)
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