Actinomycin D synergizes with Doxorubicin in triple-negative breast cancer by inducing P53-dependent cell apoptosis.

IF 3.3 3区医学 Q2 ONCOLOGY

Carcinogenesis Pub Date : 2024-04-12 DOI:10.1093/carcin/bgad086

Hong Yang, Sha Li, Wan Li, Yihui Yang, Yizhi Zhang, Sen Zhang, Yue Hao, Wanxin Cao, Fang Xu, Hongquan Wang, Guanhua Du, Jinhua Wang

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引用次数: 0

Abstract

Objectives: There are three major subtypes of breast cancer, ER+, HER2+ and triple-negative breast cancer (TNBC), namely ER-, PR-, HER2-. TNBC is the most aggressive breast cancer with poor prognosis and no target drug up to now. Actinomycin D (ActD) is a bioactive metabolite of marine bacteria that has been reported to have antitumor activity. The aim of study is to investigate whether ActD has a synergetic effect on TNBC with Doxorubicin (Dox), the major chemotherapeutic drug for TNBC, and explore the underlying mechanism.

Methods: TNBC cell lines HCC1937, MDA-MB-436 and nude mice were used in the study. Drug synergy determination, LDH assay, MMP assay, Hoechst 33342 staining, Flow cytometry, Flexible docking and CESTA assay were carried out. The expression of proteins associated with apoptosis was checked by Western blot and siRNA experiments were performed to investigate the role of P53 and PUMA induced by drugs.

Results: There was much higher apoptosis rate of cells in the ActD + Dox group than that in ActD group or Dox group. Expression of MDM2 and BCL-2 was reduced while expression of P53, PUMA and BAX were increased in the groups treated with ActD + Dox or Dox compared to the control group. Furthermore, P53 siRNA or PUMA siRNA tremendously abrogated the cell apoptosis in the groups treated by ActD, Dox and ActD + Dox. Flexible docking and CESTA showed that ActD can bind MDM2.

Conclusions: ActD had a synergetic effect on TNBC with Dox via P53-dependent apoptosis and it may be a new choice for treatment of TNBC.

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放线菌素D与阿霉素协同作用诱导p53依赖性细胞凋亡治疗三阴性乳腺癌

背景:乳腺癌有三种主要亚型:ER+、HER2+和三阴性乳腺癌(TNBC)，即ER-、PR-、HER2-。TNBC是迄今为止侵袭性最强的乳腺癌，预后较差，无靶向药物。放线菌素D (ActD)是海洋细菌的一种生物活性代谢物，据报道具有抗肿瘤活性。方法:以TNBC细胞系HCC1937、MDA-MB-436和裸鼠为研究对象，探讨ActD是否与TNBC主要化疗药物阿霉素(Dox)对TNBC有协同作用，并探讨其作用机制。进行药物协同作用测定、LDH测定、MMP测定、Hoechst 33342染色、流式细胞术、Flexible对接、CESTA测定。Western blot检测细胞凋亡相关蛋白的表达，siRNA实验研究药物诱导P53和PUMA的作用。结果:ActD + Dox组细胞凋亡率明显高于ActD组和Dox组。与对照组相比，ActD + Dox或Dox处理组MDM2和BCL-2的表达降低，P53、PUMA和BAX的表达升高。此外，P53 siRNA或PUMA siRNA显著地抑制了ActD、Dox和ActD + Dox处理组的细胞凋亡。灵活对接和CESTA表明ActD可以结合MDM2。结论:ActD通过p53依赖性细胞凋亡与Dox协同作用治疗TNBC，可能成为治疗TNBC的新选择。

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

Carcinogenesis 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

1 months

期刊介绍： Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).