Anti-allergic and anti-inflammatory effects of the Bcl-2 inhibitor ABT-737 on experimental allergic rhinitis models.

Abstract

The anti-cancer agent ABT-737 is designed specifically to inhibit anti-apoptotic proteins of the Bcl-2 family. The development of cancer has long been associated with inflammation. Here, we assess the anti-allergic and anti-inflammatory effects and the underlying molecular mechanisms of ABT-737 on allergic rhinitis (AR) using in vitro and in vivo models. In the in vitro model, the ABT-737 treatment diminished the levels of several inflammatory cytokines in this case vascular endothelial growth factor (VEGF), thymic stromal lymphopoietin (TSLP), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) by inhibiting caspase-1 and NF-κB activation in an activated human mast cell line, here HMC-1 cells. These mechanistic observations were validated in ovalbumin-sensitized AR mice. In an AR animal model, ABT-737 significantly diminished clinical symptoms of AR and the levels of AR biomarkers, specifically IgE, histamine, hypoxia-inducible factor-1α, VEGF, TSLP, IL-1β, IL-4, IL-5, IL-6, IL-13, TNF-α, intercellular adhesion molecule-1, and macrophage inflammatory protein-2. In addition, ABT-737 reduced the degree of caspase-1 activity compared to that in AR mice. Simultaneously, ABT-737 diminished the recruitment of mast cells and eosinophils into nasal mucosa tissues compared to the levels in AR mice. In conclusion, we identified new anti-allergic and anti-inflammatory effects of ABT-737. These results imply that ABT-737 can ameliorate allergic inflammatory diseases such as AR.

• Authors: Hee-Yun Kim, Hyun-Ja Jeong, Hyung-Min Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 833 Pg. 34-43 (Aug 15 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 29856968 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• ABT-737
• Anti-Allergic Agents
• Anti-Inflammatory Agents
• Biphenyl Compounds
• Cytokines
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Sulfonamides
• Vascular Endothelial Growth Factor A
• Casp1 protein, mouse
• Caspase 1

Topics

• Animals
• Anti-Allergic Agents (pharmacology, therapeutic use)
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Biphenyl Compounds (pharmacology, therapeutic use)
• Caspase 1 (metabolism)
• Cell Line
• Cell Survival (drug effects)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Mice, Inbred BALB C
• Nasal Mucosa (drug effects, metabolism)
• Nitrophenols (pharmacology, therapeutic use)
• Piperazines (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• Rhinitis, Allergic (drug therapy, metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Vascular Endothelial Growth Factor A (genetics, metabolism)