Sulforaphane Increases Drug-mediated Cytotoxicity Toward Cancer Stem-like Cells of Pancreas and Prostate
Sulforaphane Increases Drug-mediated Cytotoxicity Toward Cancer Stem-like Cells of Pancreas and Prostate
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DOI：
10.1038/mt.2010.216
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发表时间：
2011-01-01
影响因子：
12.4
通讯作者：
Herr, Ingrid
中科院分区：
文献类型：
--
作者：
Kallifatidis, Georgios;Labsch, Sabrina;Herr, Ingrid
尽管人们付出了巨大努力来开发针对胰腺癌的治疗方法，但目前还没有治愈这种高度耐药和转移性疾病的药物。西兰花复合萝卜硫素（SF）受到了相当多的关注，它被建议作为靶向胰腺癌干细胞（CSC）的联合疗法。然而，有人担心 SF 的抗氧化特性可能会干扰细胞毒性药物——如所建议的，例如。例如，维生素。因此，我们研究了使用已建立的胰腺 CSC 的联合疗法。尽管顺铂 (CIS)、吉西他滨 (GEM)、阿霉素、5-氟尿嘧啶或 SF 有效诱导细胞凋亡并阻止活力，但药物与 SF 的组合会增加毒性。同样，SF 增强了已建立的前列腺 CSC 中的药物作用，表明 SF 也增强了其他肿瘤实体中的药物细胞毒性。最重要的是，联合治疗强化了对克隆形成、球体形成和乙醛脱氢酶 1 (ALDH1) 活性以及 Notch-1 和 c-Rel 表达的抑制，表明 CSC 特征是有针对性的。在体内，联合治疗是最有效的，并且完全消除了 CSC 异种移植物的生长和肿瘤启动潜力。在正常细胞或小鼠中没有观察到明显的副作用。我们的数据表明，SF 提高了各种细胞毒性药物针对 CSC 的有效性，而不会对小鼠产生额外的毒性。
Despite intense efforts to develop treatments against pancreatic cancer, agents that cure this highly resistant and metastasizing disease are not available. Considerable attention has focused on broccoli compound sulforaphane (SF), which is suggested as combination therapy for targeting of pancreatic cancer stem cells (CSCs). However, there are concerns that antioxidative properties of SF may interfere with cytotoxic drugs-as suggested, e. g., for vitamins. Therefore we investigated a combination therapy using established pancreatic CSCs. Although cisplatin (CIS), gemcitabine (GEM), doxorubicin, 5-flurouracil, or SF effectively induced apoptosis and prevented viability, combination of a drug with SF increased toxicity. Similarly, SF potentiated the drug effect in established prostate CSCs revealing that SF enhances drug cytotoxicity also in other tumor entities. Most importantly, combined treatment intensified inhibition of clonogenicity and spheroid formation and aldehyde dehydrogenase 1 (ALDH1) activity along with Notch-1 and c-Rel expression indicating that CSC characteristics are targeted. In vivo, combination treatment was most effective and totally abolished growth of CSC xenografts and tumor-initiating potential. No pronounced side effects were observed in normal cells or mice. Our data suggest that SF increases the effectiveness of various cytotoxic drugs against CSCs without inducing additional toxicity in mice.