Mast cell activation induced by tamoxifen citrate via MRGPRX2 plays a potential adverse role in breast cancer treatment

Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm

Jiapan Gao a,b,1, Xinyue Su a,b,1, Yuxiu Zhang a,b, Xiaoyu Ma a,b, Bingxi Ren a,b, Panpan Lei a,b, Jiming Jin c, Weina Ma a,b,*

a School of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, PR China
b State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi’an 710061, PR China
c First School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xi’an 712046, PR China

ABSTRACT
Breast cancer is the most common malignant tumor endangering women’s life and health. Tamoxifen citrate (TAM) is the first-line drug of adjuvant endocrine therapy for estrogen receptor-positive (ER+) breast cancer patients. Some sporadic cases have described rare adverse reactions of TAM with potentially life-threatening dermatological manifestations, which were associated with skin allergy. Mas related G protein-coupled recep- tor X2 (MRGPRX2) on human mast cells is the key target for skin allergy. We aimed to investigate the mechanism of TAM-induced allergic reactions and their potential effects on TAM treatment for breast cancer. In our study, TAM can specifically bind with MRGPRX2, which was mainly driven by hydrophobic force. TAM formed hydrogen bonds with TRP243, TRP248, and GLU164 residues in MRGPRX2. TAM induced calcium mobilization and degranulation of mast cells via MRGPRX2. Besides, TAM induced passive cutaneous anaphylaxis and active systemic anaphylaxis in C57BL/6 mice. The release of β-hexosaminidase, histamine, tumor necrosis factor-α, monocyte chemoattractant protein 1, and interleukin-8 were increased by TAM in vitro and in vivo. Furthermore, we found that MCF-7 and T-47D breast cancer cells can recruit mast cells to adjacent cancerous tissues. Besides, mast cell activation induced by TAM via MRGPRX2 significantly promoted the proliferation and migration of MCF-7 and T-47D cells, which can be effectively reversed by mast cell membrane stabilizer clarithromycin and MRGPRX2 silencing. This study proposed an anti-allergic therapeutic strategy for breast cancer treatment with TAM, while also the potential of MRGPRX2 as an adjunctive target.

Phytother Res. 2023 Aug;37(8):3572-3582. doi: 10.1002/ptr.7835. Epub 2023 Apr 28.

Silibinin attenuated pseudo-allergic reactions and mast cell degranulation via PLCγ and PI3K/Akt signaling pathway

Yuejin Wang ¹, Shiting Hu ¹, Baowen Dang ¹, Yonghui Zhang ¹, Guodong Zheng ¹, Chenrui Zhao ¹, Yihan Huang ¹, Tao Zhang ¹

Affiliations expand

• PMID: 37115717
• DOI: 10.1002/ptr.7835

Abstract

Anaphylaxis is a type of potentially fatal hypersensitivity reaction resulting from the activation of mast cells. Many endogenous or exogenous factors could cause this reaction. Silibinin is the main chemical component of silymarin and has been reported to have pharmacological activities. However, the anti-allergic reaction effect of silibinin has not yet been investigated. This study aimed to evaluate the effect of silibinin to attenuate pseudo-allergic reactions in vivo and to investigate the underlying mechanism in vitro. In this study, calcium imaging was used to assess Ca²⁺ mobilization. The levels of cytokines and chemokines, released by stimulated mast cells, were measured using enzyme immunoassay kits. The activity of silibinin was evaluated in a mouse model of passive cutaneous anaphylaxis (PCA). Western blotting was used to explore the related molecular signaling pathways. In results, silibinin markedly inhibited mast cell degranulation, calcium mobilization, and preventing the release of cytokines and chemokines in a dose-dependent manner via the PLCγ and PI3K/Akt signaling pathway. Silibinin also attenuated PCA in a dose-dependent manner. In summary, silibinin has an anti-pseudo-allergic pharmacological activity, which makes it a potential candidate for the development of a novel agent to arrest pseudo-allergic reactions.

Keywords: PI3K/Akt; mast cell; pseudo-allergy; silibinin.

https://pubmed.ncbi.nlm.nih.gov/37115717/

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists

[The journal of allergy and clinical immunology] July 2, 2024

Background: Mas-related G protein–coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell–mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo.
Objective: We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell–mediated disease.

Methods: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell–derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout and Mrgprb2em(MRGPRX2)
transgenic human MRGPRX2 knock-in mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples.

Results: MRGPRX2 antagonists potently inhibited agonist- induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist- induced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin.

Conclusions: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

Pain. 2023 Jun 1; doi: 10.1097/j.pain.0000000000002824. 

Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice

Kenta Furutani ¹, Ouyang Chen ^1 2, Aidan McGinnis ¹, Yuqing Wang ¹, Charles N Serhan ³, Trond Vidar Hansen ⁴, Ru-Rong Ji ^1 2 5

Affiliations expand

• PMID: 36378290
• PMCID: PMC10182233 (available on 2024-06-01)
• DOI: 10.1097/j.pain.0000000000002824

Abstract

Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.