Innovative role of the antidepressant imipramine in esophageal squamous cell carcinoma treatment: Promoting apoptosis and protective autophagy

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2024.113969

Shihao Bao , Yifan Zhang , Jingtong Zeng , Bo Zhang , Hanqing Wang , Xianjie Li , Hao Zhang , Yuan Cheng , Wei Xia , Xiaohong Xu , Lingling Zu , Song Xu , Zuoqing Song

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引用次数: 0

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent malignant tumors; it is associated with dismal prognosis, and effective therapeutic agents are lacking. Depression is prevalent concern among cancer patients and is linked to diminished quality of life, poor adherence to treatment, heightened risk of suicide, and poorer prognosis. Imipramine (IM) is a tricyclic antidepressant with anti-inflammatory activity. Recent reports have indicated antitumor effects of IM in various cancers, although its role in ESCC remains unclear.

Methods

The depression status of patients with ESCC was graded with the Patient Health Questionnaire-9, and the effects of antidepressants (moclobemide, milnacipran, venlafaxine, escitalopram, amitriptyline, trazodone, fluvoxamine, and IM) on cell viability were evaluated through CCK-8 assays. The effects of IM on cell proliferation were evaluated through clone formation assays, whereas Transwell assays were used to assess effects on ESCC cell migration and invasion. IM-induced apoptosis was confirmed with annexin V-FITC/Caspase-3 assays, and immunofluorescence staining was used to investigate the formation of IM-induced autophagosomes. Furthermore, western blotting analysis was conducted to determine the expression levels of apoptosis- and autophagy-related proteins. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Finally, we investigated the influence of IM on tumor progression in vivo in a xenograft model.

Results

The PHQ-9 scores of patients with ESCC were higher than those of healthy controls and positively correlated with the TNM stage of ESCC. Among the antidepressants examined in our study, IM demonstrated the most potent inhibitory effect on ESCC cell viability, and effectively suppressed the proliferation, migration, and invasion of ESCC cells. Additionally, IM treatment induced apoptosis and autophagy in ESCC cells. Furthermore, blocking autophagy with chloroquine (CQ) intensified IM-induced apoptosis, thereby suggesting a protective role of cellular autophagy against apoptosis. RNA-seq results indicated that the Hippo pathway was associated with IM treatment. Upregulation of YAP reversed the apoptosis and autophagy triggered by IM, and targeting YAP intensified this effect. Finally, in animal experiments, IM hindered the growth of ESCC cells and promoted apoptosis and autophagy in tumors while causing minimal toxicity.

Conclusion

Our findings provide the first reported evidence that IM triggers apoptosis and protective autophagy in ESCC cells via the Hippo signaling pathway, thus suggesting that IM may offer a promising therapeutic approach for patients with ESCC and depression.

查看原文本刊更多论文

抗抑郁药丙咪嗪在食管鳞癌治疗中的创新作用：促进细胞凋亡和保护性自噬。

背景：食管鳞癌（ESCC）是最常见的恶性肿瘤之一；该病预后差，缺乏有效的治疗药物。抑郁症是癌症患者普遍关注的问题，它与生活质量下降、治疗依从性差、自杀风险增加和预后较差有关。丙咪嗪（IM）是一种具有抗炎活性的三环抗抑郁药。最近的报道表明IM在多种癌症中的抗肿瘤作用，尽管其在ESCC中的作用尚不清楚。方法：采用《患者健康问卷-9》对ESCC患者的抑郁状态进行分级，并采用CCK-8法评价抗抑郁药（莫氯贝胺、米那西普兰、文拉法辛、艾司西酞普兰、阿米替林、曲唑酮、氟伏沙明和IM）对细胞活力的影响。通过克隆形成实验评估IM对细胞增殖的影响，通过Transwell实验评估IM对ESCC细胞迁移和侵袭的影响。annexin V-FITC/Caspase-3检测证实im诱导的细胞凋亡，免疫荧光染色观察im诱导的自噬体的形成。此外，通过western blotting分析确定凋亡和自噬相关蛋白的表达水平。RNA测序（RNA-seq）检测信号通路的变化。最后，我们在异种移植模型中研究了IM对肿瘤进展的影响。结果：ESCC患者PHQ-9评分高于健康对照组，且与ESCC TNM分期呈正相关。在我们研究的抗抑郁药物中，IM对ESCC细胞活力的抑制作用最强，可以有效抑制ESCC细胞的增殖、迁移和侵袭。此外，IM处理诱导ESCC细胞凋亡和自噬。此外，用氯喹（chloroquine， CQ）阻断自噬可增强im诱导的细胞凋亡，从而提示细胞自噬对细胞凋亡具有保护作用。RNA-seq结果表明Hippo通路与IM治疗有关。上调YAP可逆转IM引发的细胞凋亡和自噬，靶向YAP可强化这一作用。最后，在动物实验中，IM抑制了ESCC细胞的生长，促进了肿瘤细胞的凋亡和自噬，而毒性很小。结论：我们的研究结果首次提供了IM通过Hippo信号通路触发ESCC细胞凋亡和保护性自噬的证据，这表明IM可能为ESCC合并抑郁症患者提供了一种有希望的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.