Antitumor activity of arsenite in combination with tetrandrine against human breast cancer cell line MDA-MB-231 in vitro and in vivo.
Antitumor activity of arsenite in combination with tetrandrine against human breast cancer cell line MDA-MB-231 in vitro and in vivo.
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DOI：
10.1186/s12935-018-0613-0
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发表时间：
2018
影响因子：
5.8
通讯作者：
Takagi N
中科院分区：
文献类型：
--
作者：
Yuan B;Yao M;Wang X;Sato A;Okazaki A;Komuro H;Hayashi H;Toyoda H;Pei X;Hu X;Hirano T;Takagi N
三阴性乳腺癌（TNBC）是最难治疗的乳腺癌亚型之一，因为它具有侵袭性、转移性和缺乏靶向治疗。三价砷的衍生物（亚砷酸盐，AsIII）对急性早幼粒细胞白血病有显著的临床疗效，对乳腺癌细胞有抑制作用。为了提供新的见解的发展，新的治疗策略，抗肿瘤活性的AsIII和粉防己碱（Tetra），中国植物衍生的生物碱，对TNBC细胞系MDA-MB-231在体外和体内进行了研究。采用细胞活力、乳酸脱氢酶渗漏和细胞周期测定评价细胞毒性。用蛋白质印迹法分析细胞增殖和死亡相关基因的改变。在裸鼠中使用MDA-MB-231异种移植物研究单独或与Tetra组合的AsIII的体内抗肿瘤活性。在细胞中观察到两种药物的协同细胞毒作用。体内研究还表明，AsIII和Tetra的联合给药显著降低了肿瘤体积和重量，直接支持其体外抗肿瘤活性。长期联合给药后未观察到死亡和体重减轻，表明其耐受性良好。在用联合方案处理的细胞中观察到与FOXO 3a、p27沿着上调以及Cyclin D1表达降低相关的S期停滞。在AsIII和Tetra联合给药的小鼠肿瘤组织中观察到p21表达显著上调，磷酸化FOXO 3a和细胞周期蛋白D1表达下调。在体外和体内联合治疗中观察到自噬诱导。添加渥曼青霉素，一种有效的自噬抑制剂，显着拯救MDA-MB-231细胞的AsIII和Tetra的细胞毒性。S期阻滞、自噬和坏死性细胞死亡有助于AsIII和Tetra联合方案的杀细胞作用。考虑到我们先前的研究显示联合方案在雌激素受体阳性乳腺癌细胞系MCF-7中的协同细胞毒性作用，这些结果表明，AsIII加Tetra的联合方案的开发可能为不同类型的乳腺癌患者提供许多益处。
Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its aggressive, metastatic behavior, and a lack of a targeted therapy. Trivalent arsenic derivatives (arsenite, AsIII) with remarkable clinical efficacy in acute promyelocytic leukemia has been demonstrated to exhibit inhibitory effect against breast cancer cells. To provide novel insight into the development of new therapeutic strategies, antitumor activity of AsIII and tetrandrine (Tetra), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 in vitro and in vivo was investigated. Cytotoxicity was evaluated using cell viability, lactate dehydrogenase leakage and cell cycle assay. Alterations of genes related to cell proliferation and death were analyzed using western blotting. In vivo antitumor activity of AsIII alone or in combination with Tetra was studied using MDA-MB-231 xenografts in nude mice. Synergistic cytotoxic effects of two drugs were observed in the cells. In vivo study also showed that co-administration of AsIII and Tetra significantly reduced tumor volume and weight, directly supporting its in vitro antitumor activity. No deaths and reduction of body-weight were observed after a long-term co-administration, indicating its good tolerability. S-phase arrest associated with the upregulation of FOXO3a, p27 along with decreased Cyclin D1 expression was observed in the cells treated with the combined regimen. A substantial upregulated p21 expression and downregulated phospho-FOXO3a and Cyclin D1 expression was observed in the tumor tissues of mice co-administered with AsIII and Tetra. Autophagy induction was observed in the combination treatment in vitro and in vivo. The addition of wortmannin, a potent autophagy inhibitor, significantly rescued MDA-MB-231 cells from their cytotoxicity of AsIII and Tetra. S-phase arrest, autophagic and necrotic cell death contribute to the cytocidal effects of the combined regimen of AsIII and Tetra. Considering our previous study showing synergistic cytotoxic effects of the combined regimen in estrogen receptor-positive breast cancer cell line MCF-7, these results suggest that development of the combination regimen of AsIII plus Tetra may offer many benefits to patients with different types of breast cancer.
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