Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma.
Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma.
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DOI：
10.1158/1078-0432.ccr-15-2256
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发表时间：
2016-07-15
期刊：
影响因子：
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通讯作者：
Kebebew E
中科院分区：
文献类型：
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作者：
Satoh K;Zhang L;Zhang Y;Chelluri R;Boufraqech M;Nilubol N;Patel D;Shen M;Kebebew E
肾上腺皮质癌（ACC）是一种罕见的侵袭性癌症，目前尚无有效的治疗方法可用于局部晚期和转移性ACC。药物再利用是一种新兴的方法，用于确定现有药物的新适应症，特别是对于罕见的癌症，如ACC。本研究的目的是使用定量高通量筛选来鉴定对ACC具有抗肿瘤活性的药物。在3种ACC细胞系BD140A、SW-13和NCI-H295R上筛选了4292种化合物。共鉴定出21种活性化合物，对3种细胞系的疗效均为80%。其中，与现有抗acc药物相比，氯硝柳胺的疗效更高，IC50更低。然后，我们验证了氯硝胺在所有三种ACC细胞系中抑制细胞增殖。接下来，我们研究了氯硝胺抑制ACC细胞增殖的机制，发现它诱导caspase依赖性细胞凋亡和G1细胞周期阻滞。奈洛沙胺还能减少细胞迁移，降低上皮细胞向间质转化的介质水平，如n -钙粘蛋白和vimentin。此外，氯硝柳胺治疗导致β-catenin的表达降低。我们还评估了氯硝柳胺对ACC细胞系能量代谢的影响，发现它导致线粒体解偶联。在小鼠体内，氯硝柳胺治疗抑制ACC肿瘤生长，未观察到毒性。我们的研究结果表明，氯硝柳胺通过抑制ACC中多种改变的细胞通路和细胞代谢而具有抗ACC活性。我们的结果为在ACC临床试验中评估氯硝柳胺治疗提供了临床前依据。
Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC.