利用 I 类靶向 HDAC 抑制剂 bocodepsin/OKI-179 促进细胞凋亡,克服三阴性乳腺癌对多柔比星的耐药性

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-03-01 DOI:10.1186/s13058-024-01799-5
Stephen G. Smoots, Anna R. Schreiber, Marilyn M. Jackson, Stacey M. Bagby, Adrian T A. Dominguez, Evan D. Dus, Cameron A. Binns, Morgan MacBeth, Phaedra A. Whitty, Jennifer R. Diamond, Todd M. Pitts
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引用次数: 0

摘要

三阴性乳腺癌(TNBC)是一种侵袭性乳腺癌亚型,预后较差。多柔比星是 TNBC 标准根治疗法的一部分,但化疗耐药性仍是一个重要的临床挑战。Bocodepsin(OKI-179)是一种小分子I类组蛋白去乙酰化酶(HDAC)抑制剂,可在TNBC临床前模型中促进细胞凋亡。本研究的目的是在TNBC临床前模型中研究bocodepsin和多柔比星的组合,并评估其对末端细胞命运(包括凋亡和衰老)的影响。用多柔比星处理 TNBC 细胞系,并使用 CellTiter-Glo 评估增殖情况和确定多柔比星的敏感性。用 OKI-005(bocodepsin 的体外版本)和多柔比星处理部分细胞系,并用流式细胞术评估细胞增殖、Annexin V/PI 测定的细胞凋亡和细胞周期。免疫印迹法用于评估细胞凋亡、细胞周期停滞和衰老介质的变化。衰老通过衰老相关的β-半乳糖苷酶检测法进行测量。用bocodepsin、多柔比星或联合疗法处理MDA-MB-231异种移植体内模型,并评估其对肿瘤生长的抑制作用。 在CAL-51细胞系中进行p53的shRNA敲除,并评估增殖、细胞凋亡和衰老对联合疗法的反应。OKI-005和多柔比星在TNBC细胞系中具有协同抗增殖活性,与p53突变状态无关。联合用药可增加细胞凋亡,减少衰老。在体内,与任何一种单药相比,联合用药都能增加对肿瘤生长的抑制作用。在多柔比星中加入波可地平,可在体外产生协同抗增殖活性,在体内改善肿瘤生长抑制,并促进细胞凋亡,这使其成为克服 TNBC 多柔比星耐药性的一种很有前景的联合疗法。Bocodepsin 目前正处于临床开发阶段,与其他 HDAC 抑制剂相比,它具有良好的毒性特征,支持在 TNBC 患者中评估这种联合用药的可行性。
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Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence. TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated β-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment. OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro. The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
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发文量
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期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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