Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling.

IF 5.3 2区医学 Q1 ONCOLOGY Cancer Cell International Pub Date : 2024-06-29 DOI:10.1186/s12935-024-03400-7

Irene Dell'Anno, Federica Morani, Simone Patergnani, Antonio Daga, Paolo Pinton, Carlotta Giorgi, Luciano Mutti, Federica Gemignani, Stefano Landi

{"title":"Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling.","authors":"Irene Dell'Anno, Federica Morani, Simone Patergnani, Antonio Daga, Paolo Pinton, Carlotta Giorgi, Luciano Mutti, Federica Gemignani, Stefano Landi","doi":"10.1186/s12935-024-03400-7","DOIUrl":null,"url":null,"abstract":"Background: Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model.Methods: In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves.Results: After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076).Conclusions: Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218145/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell International","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12935-024-03400-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model.

Methods: In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves.

Results: After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca²⁺ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076).

Conclusions: Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

溴甲烷通过调节ERK1/2和p38通路以及线粒体解偶联抑制恶性胸膜间皮瘤的进展。

背景：恶性胸膜间皮瘤（MPM）是一种罕见的恶性肿瘤，预后不良。目前的疗法并不理想，迫切需要新的治疗方法。在之前的药物筛选中，我们发现噻唑溴铵（TB）是对 MPM 细胞最有效的化合物之一。由于人们对 TB 的生物效应知之甚少，在这项工作中，我们摒弃了之前研究中的一些提示，并对几种假设进行了研究。此外，我们还在体内异种移植啮齿动物模型中评估了 TB 的功效：我们对五种 MPM（Mero-14、Mero-25、Ren、NCI-H28、MSTO-211H）和一种 SV40-immortalized 间皮细胞系（MeT-5A）进行了体外评估。我们评估了 TB 影响增殖、凋亡、线粒体功能和代谢以及甲羟戊酸途径的能力。我们对骨髓瘤异种移植 NOD-SCID 小鼠进行了体内试验（腹腔注射 4 毫克/千克，每周两次，连续 4 周），并用 Kaplan-Meier 曲线分析了总存活率：结果：TB治疗后，我们观察到ERK 1/2磷酸化被抑制，BAX表达和p38磷酸化增加。结核影响线粒体和细胞质中的 Ca2+ 平衡，调节线粒体功能、呼吸和 ATP 生成以及甲羟戊酸途径。体内研究显示，结核病治疗组与药物对照组相比，总存活率有所提高（P = 0.0076）：体外和体内研究结果都证实了结核病对骨髓瘤的影响，并揭示了具有转化潜力的新靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.