Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics
Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics
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DOI：
10.1158/0008-5472.can-10-0066
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发表时间：
2010-06-15
期刊：
影响因子：
11.2
通讯作者：
Herr, Ingrid
中科院分区：
文献类型：
--
作者：
Rausch, Vanessa;Liu, Li;Herr, Ingrid
最近的证据表明，胰腺癌和其他实体肿瘤包含一个能够广泛自我更新的致瘤细胞亚群，这有助于转移和治疗抵抗。索拉非尼（Sorafenib， SO）是一种治疗晚期肾癌和肝癌的新型多激酶抑制剂。我们在此报告了SO对胰腺癌干细胞（CSC）的靶向作用，以及一种增强这种作用的策略的发展。虽然给药SO降低了克隆原性、球状体形成、醛脱氢酶1 （ALDH1）活性、免疫缺陷小鼠的生长、增殖、血管生成和诱导凋亡，但我们观察到SO诱导的nf - κ B活化与球状体的存活和再生有关。为了增强SO消除CSC特征，我们用萝卜硫素（SF）共处理细胞。这种西兰花异硫氰酸酯最近被描述为通过下调nf - κ B活性来消除胰腺CSCs，而不会引起毒副作用。在联合处理下，SF完全根除了so诱导的NF-kappa B结合，这与克隆原性、球状体形成、ALDH1活性、迁移能力和诱导凋亡有关。在体内，联合治疗以协同方式减小肿瘤大小。这是由于诱导细胞凋亡，抑制增殖和血管生成，以及so诱导的参与上皮-间质转化的蛋白表达下调。我们的数据表明SF可能适合于增加SO对CSCs的靶向性。癌症Res;70 (12);5004 - 13所示。AACR (C) 2010。
Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-kappa B associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-kappa B activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-kappa B binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO. Cancer Res; 70(12); 5004-13. (C)2010 AACR.