组胺H1受体:胰腺导管腺癌的潜在治疗靶点。

IF 3.8 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Cristina Salmerón, Elena Tomás Bort, Krishna Sriram, Mehrak Javadi-Paydar, Jane E Smitham, Kimberly Pham, Richard P Grose, Peter J McCormick, Anna DiNardo, Jonathan Weitz, Hervé Tiriac, Andrew M Lowy, Paul A Insel
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引用次数: 0

摘要

诊断为胰腺导管腺癌(PDAC)的患者的5年生存率很低(约13%)。因此,迫切需要新的、有效的、理想的、毒性更小的治疗方法。流行病学研究发现,处方h1抗组胺药的PDAC患者生存率提高。组胺H1受体(HRH1)是一种G蛋白偶联受体,被批准的H1抗组胺药阻断,与正常胰腺相比,PDAC肿瘤中组胺H1受体(HRH1)的表达增加了20倍。在这里,我们使用生物信息学和分子生物学技术来确定HRH1在PDAC肿瘤微环境中的细胞定位,评估HRH1激活的功能反应,并确定其在PDAC中的潜在生物学作用。我们发现HRH1主要在人类和KPC小鼠(PDAC小鼠)的PDAC肿瘤的癌细胞中表达,并通过G蛋白q/11信号增加细胞内Ca2+。HRH1激活增加PDAC癌细胞的迁移和侵袭。口服非索非那定是一种h1抗组胺药,在KPC小鼠的肿瘤中具有生物可利用性,与对照KPC小鼠相比,其胰腺肿瘤组织重量更小,免疫调节(白细胞介素6和PD-1)和纤维化(Col1A1)基因的表达更低。因此,PDAC癌细胞表达HRH1,在体外和体内都有功能,这表明重新使用已批准的h1抗组胺药可能是一种有效且安全的治疗PDAC患者的方法。意义声明:胰腺导管腺癌(PDAC)的5年生存率约为13%,强调了对新疗法的需求。与较差生存率相关的HRH1(组胺)受体在PDAC肿瘤中表达上调。本研究发现HRH1在PDAC细胞中发挥功能,通过Gq/11增加细胞内Ca2+并促进肿瘤反应。用h1抗组胺药治疗的KPC小鼠胰腺重量减轻,PDAC肿瘤的促炎和纤维化标志物降低。因此,HRH1可能是重新利用已批准的h1抗组胺药治疗PDAC的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Histamine H1 Receptor: A potential therapeutic target for pancreatic ductal adenocarcinoma.

Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a dismal 5-year survival (∼13%). Thus, new, effective, and ideally, less toxic therapies are desperately needed. Epidemiologic studies have found that patients with PDAC prescribed H1-antihistamines have improved survival. Expression of the histamine H1 receptor (HRH1), a G protein-coupled receptor which is blocked by approved H1-antihistamines, is increased by ∼20-fold in PDAC tumors compared with normal pancreas. Here, we used bioinformatic and molecular biological techniques to identify the cellular localization of HRH1 in the PDAC tumor microenvironment, assess functional responses to HRH1 activation, and define its potential biological roles in PDAC. We found that HRH1 is primarily expressed in cancer cells of PDAC tumors in humans and KPC mice (mice engineered to develop PDAC) and signals via G protein q/11 to increase intracellular Ca2+. HRH1 activation increases migration and invasion by PDAC cancer cells. Orally administered fexofenadine, an H1-antihistamine, was bioavailable in the tumors of KPC mice and yielded smaller pancreatic tumor tissue weights and lower expression of immunomodulatory (interleukin 6 and PD-1) and fibrotic (Col1A1) genes than in vehicle-control KPC mice. Thus, PDAC cancer cells express HRH1, which is functional in vitro and in vivo, suggesting that the repurposing of approved H1-antihistamines may be an efficacious and safe therapeutic approach for patients with PDAC. SIGNIFICANCE STATEMENT: Pancreatic ductal adenocarcinoma (PDAC) has a ∼13% 5-year survival rate, highlighting the need for new therapies. The HRH1 (histamine) receptor, associated with poorer survival, is upregulated in PDAC tumors. This study found that HRH1 is functional in PDAC cells, increasing intracellular Ca2+ via Gq/11 and promoting tumorigenic responses. KPC mice treated with an H1-antihistamine have reduced pancreas weight and lower proinflammatory and fibrotic markers in PDAC tumors. Thus, HRH1 may be a potential target for repurposing approved H1-antihistamines to treat PDAC.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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