Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells

被引：41

作者：

Gu, Zhi-Min ^{[1
,2
]}

Wu, Ying-Li ^{[1
]}

Zhou, Mei-Yi ^{[1
]}

Liu, Chuan-Xu ^{[1
]}

Xu, Han-Zhang ^{[1
]}

Yan, Hua ^{[3
]}

Zhao, Yong ^{[4
]}

Huang, Ying ^{[1
]}

Sun, Han-Dong ^{[4
]}

Chen, Guo-Qiang ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Dept Pathophysiol, Shanghai Univ E Inst,Chem Biol Div,Sch Med, Key Lab Cell Differentiat & Apoptosis Chinese Min, Shanghai 200025, Peoples R China

[2] Chinese Acad Sci, Inst Hlth Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China

[3] SJTU SM, Rui Jin Hosp, Dept Hematol, Shanghai, Peoples R China

[4] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W, Yunnan, Peoples R China

来源：

BLOOD | 2010年 / 116卷 / 24期

基金：

中国国家自然科学基金;

关键词：

ACUTE PROMYELOCYTIC LEUKEMIA; RAR-ALPHA; PML/RAR-ALPHA; TRANSCRIPTIONAL ACTIVITY; GROWTH ARREST; DEGRADATION; MATURATION; GENE; NB4; EXPRESSION;

D O I：

10.1182/blood-2010-02-267963

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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)

引用

页码：5289 / 5297

页数：9