Celastrol inhibits lung infiltration in differential syndrome animal models by reducing TNF-α and ICAM-1 levels while preserving differentiation in ATRA-induced acute promyelocytic leukemia cells

Li-min Xu; Yue-juan Zheng; Ying Wang; Yang Yang; Fan-fan Cao; Bin Peng; Xiong-fei Xu; Hua-zhang An; Ao-xiang Zheng; Deng-hai Zhang; Georges Uzan; Yi-zhi Yu

doi:10.1371/journal.pone.0105131

Celastrol inhibits lung infiltration in differential syndrome animal models by reducing TNF-α and ICAM-1 levels while preserving differentiation in ATRA-induced acute promyelocytic leukemia cells

PLoS One. 2014 Aug 12;9(8):e105131. doi: 10.1371/journal.pone.0105131. eCollection 2014.

Authors

Li-min Xu¹, Yue-juan Zheng², Ying Wang³, Yang Yang⁴, Fan-fan Cao³, Bin Peng³, Xiong-fei Xu⁴, Hua-zhang An⁴, Ao-xiang Zheng⁴, Deng-hai Zhang⁵, Georges Uzan⁵, Yi-zhi Yu⁴

Affiliations

¹ National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China; Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China.
² National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China; Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
³ Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China.
⁴ National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
⁵ Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China; U972, Inserm, Hôpital Paul Brousse, Paris, France.

Abstract

All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / drug effects*
Cell Line, Tumor
Humans
Intercellular Adhesion Molecule-1 / genetics
Intercellular Adhesion Molecule-1 / metabolism
Leukemia, Promyelocytic, Acute / drug therapy*
Leukemia, Promyelocytic, Acute / metabolism
Leukemia, Promyelocytic, Acute / pathology
Lung / drug effects*
Lung / metabolism
Lung / pathology
MAP Kinase Signaling System / drug effects
Male
Mice
Mice, Inbred NOD
Mice, SCID
Pentacyclic Triterpenes
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism
Syndrome
Tretinoin / adverse effects*
Tretinoin / therapeutic use
Triterpenes / pharmacology*
Tumor Necrosis Factor-alpha / metabolism

Substances

Pentacyclic Triterpenes
RNA, Messenger
RNA, Neoplasm
Triterpenes
Tumor Necrosis Factor-alpha
Intercellular Adhesion Molecule-1
Tretinoin
celastrol

Grants and funding

This work is supported by the National Key Development Program for Basic Research of China (No. 2010CB529901) and the Key Project of Chinese Ministry of Health (No. 2012ZX10002006-001-004) to YZY, the Project of Excellent Academic Leader in Medicine of Shanghai (No. XBR2011054) to DHZ, the Medical Project of Shanghai Pudong District (No. PKJ2011-Y11) to LMX, and the National Natural Science Foundation of China (No. 31100619) to YJZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.