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Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications.

重新利用 5-羟色胺激动剂替加色罗作为黑色素瘤的抗癌药物: 分子机制和临床意义。

  • 影响因子:5.34
  • DOI:10.1186/s13046-020-1539-7
  • 作者列表:"Liu W","Stachura P","Xu HC","Umesh Ganesh N","Cox F","Wang R","Lang KS","Gopalakrishnan J","Häussinger D","Homey B","Lang PA","Pandyra AA
  • 发表时间:2020-02-21
Abstract

BACKGROUND:New therapies are urgently needed in melanoma particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. METHODS:Drug screening, IC50 determinations as well as synergy assays were detected by the MTT assay. Apoptosis using Annexin V and 7AAD staining was assessed using flow cytometry. TUNEL staining was performed using immunocytochemistry. Changes in phosphorylation of key molecules in PI3K/Akt/mTOR and other relevant pathways were detected by western blot as well as immunocytochemistry. To assess in vivo anti-tumor activity of Tegaserod, syngeneic intravenous and subcutaneous melanoma xenografts were used. Immunocytochemical staining was performed to detect expression of active Caspase-3, cleaved Caspase 8 and p-S6 in tumors. Evaluation of immune infiltrates was carried out by flow cytometry. RESULTS:Using a screen of 770 pharmacologically active and/or FDA approved drugs, we identified Tegaserod (Zelnorm, Zelmac) as a compound with novel anti-cancer activity which induced apoptosis in murine and human malignant melanoma cell lines. Tegaserod (TM) is a serotonin receptor 4 agonist (HTR4) used in the treatment of irritable bowel syndrome (IBS). TM's anti-melanoma apoptosis-inducing effects were uncoupled from serotonin signaling and attributed to PI3K/Akt/mTOR signaling inhibition. Specifically, TM blunted S6 phosphorylation in both BRAFV600E and BRAF wildtype (WT) melanoma cell lines. TM decreased tumor growth and metastases as well as increased survival in an in vivo syngeneic immune-competent model. In vivo, TM also caused tumor cell apoptosis, blunted PI3K/Akt/mTOR signaling and decreased S6 phosphorylation. Furthermore TM decreased the infiltration of immune suppressive regulatory CD4+CD25+ T cells and FOXP3 and ROR-γt positive CD4+ T cells. Importantly, TM synergized with Vemurafenib, the standard of care drug used in patients with late stage disease harboring the BRAFV600E mutation and could be additively or synergistically combined with Cobimetinib in both BRAFV600E and BRAF WT melanoma cell lines in inducing anti-cancer effects. CONCLUSION:Taken together, we have identified a drug with anti-melanoma activity in vitro and in vivo that has the potential to be combined with the standard of care agent Vemurafenib and Cobimetinib in both BRAFV600E and BRAF WT melanoma.

摘要

背景: 黑色素瘤迫切需要新的治疗方法,尤其是对免疫疗法和激酶抑制剂无反应的晚期患者。 方法: 采用 MTT 法检测药物筛选、 IC50 测定及协同作用试验。使用 Annexin V 和 7AAD 染色的细胞凋亡使用流式细胞术进行评估。使用免疫细胞化学进行 TUNEL 染色。Western blot 和免疫细胞化学检测 PI3K/Akt/mTOR 等相关通路中关键分子磷酸化的变化。为了评估替加色罗的体内抗肿瘤活性,使用同基因静脉和皮下黑色素瘤异种移植物。免疫细胞化学染色检测肿瘤中活性 Caspase-3 、 cleaved Caspase 8 和 p-S6 的表达。通过流式细胞术进行免疫浸润的评价。 结果: 使用 770 个药理学活性和/或 FDA 批准的药物的筛选,我们确定了替加色罗 (Zelnorm,Zelmac) 作为一种具有新型抗癌活性的化合物,诱导小鼠和人恶性黑色素瘤细胞系凋亡。替加色罗 (TM) 是一种 5-羟色胺受体 4 激动剂 (HTR4),用于治疗肠易激综合征 (IBS)。TM 的抗黑色素瘤凋亡诱导作用与 5-羟色胺信号解偶联,归因于 PI3K/Akt/mTOR 信号抑制。具体而言,TM 在 BRAFV600E 和 BRAF 野生型 (WT) 黑色素瘤细胞系中均钝化了 S6 磷酸化。TM 减少了体内同基因免疫活性模型中的肿瘤生长和转移,并增加了生存率。在体内,TM 还引起肿瘤细胞凋亡,PI3K/Akt/mTOR 信号减弱,S6 磷酸化降低。此外,TM 降低了免疫抑制性调节性 CD4 + CD25 + T 细胞和 FOXP3 和 ROR-γ T 阳性 CD4 + T 细胞的浸润。重要的是,TM 与 Vemurafenib 协同作用, 在携带 BRAFV600E 突变的晚期疾病患者中使用的标准护理药物,并且可以在 BRAFV600E 和 BRAF WT 黑色素瘤细胞系中与 Cobimetinib 相加或协同组合诱导抗癌作用。。 结论: 综合起来看, 我们已经确定了一种具有体外和体内抗黑色素瘤活性的药物,该药物有可能与标准护理剂 Vemurafenib 和 Cobimetinib 在 BRAFV600E 和 BRAF WT 黑色素瘤中联合使用。

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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.039
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

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