Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells.
Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells.
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DOI：
10.1158/1535-7163.mct-11-0999
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发表时间：
2012-04
影响因子：
5.7
通讯作者：
Anant S
中科院分区：
文献类型：
--
作者：
Ponnurangam S;Mammen JM;Ramalingam S;He Z;Zhang Y;Umar S;Subramaniam D;Anant S
癌症干细胞（CSC）与电离辐射（IR）和化疗的抗性有关。和厚朴是一种双酚类化合物，在传统中药中用于治疗各种疾病。在这项研究中，我们确定了和厚朴酚提高结肠癌干细胞对IR的敏感性的能力。和厚朴酚和IR的组合抑制增殖和集落形成，同时诱导培养的结肠癌细胞凋亡。球状体的数量和大小也减少，这与CSC标志物蛋白DCLK 1的表达减少有关。流式细胞术研究证实，和厚朴酚-IR组合减少了DCLK 1+细胞的数量。此外，活化的Notch-1、其配体Jagged-1和下游靶基因Hes-1的水平降低。此外，Notch-1激活γ-分泌酶复合物的组分早老素1、Nicastrin、Pen 2和APH-1的表达也受到抑制。另一方面，当Notch胞内结构域表达时，honoklasts效应减轻。为了确定和厚朴酚-IR组合对体内肿瘤生长的影响，将和厚朴酚腹膜内施用到裸鼠肿瘤异种移植物中并暴露于IR。和厚朴酚-IR组合显著抑制肿瘤异种移植物生长。此外，异种移植组织中DCLK 1和Notch信号相关蛋白的水平降低。总之，这些数据表明，和诺碱是结肠癌生长的有效抑制剂，其通过抑制γ-分泌酶复合物和Notch信号通路靶向干细胞。这些研究保证了进一步的临床评价和诺明和IR的组合用于治疗结肠癌。
Cancer stem cells (CSCs) are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese Medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon CSCs to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of CSC marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1 and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, Presenilin 1, Nicastrin, Pen2 and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers.