Inhibition of GSK-3β activity attenuates proliferation of human colon cancer cells in rodents
Inhibition of GSK-3β activity attenuates proliferation of human colon cancer cells in rodents
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DOI：
10.1111/j.1349-7006.2007.00545.x
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发表时间：
2007-09-01
期刊：
影响因子：
5.7
通讯作者：
Minamoto, Toshinari
中科院分区：
文献类型：
--
作者：
Shakoori, Abbas;Mai, Wei;Minamoto, Toshinari
作者最近发现糖原合成酶-3β(GSK-3β)参与了结肠癌细胞的存活和增殖，这促使我们研究GSK-3β抑制是否改变了体内结肠癌细胞的增殖。4只或5只裸鼠(Balb/c，Nu/Nu)皮下移植人结肠癌细胞，分别给予二甲基亚砜或不同剂量(1、2、5 mg/kg体重)的小分子GSK-3β抑制剂(SB-216763和AR-A014418)，每周3次，共5周。与对照组DMSO(GSK-3β抑制剂的稀释液)相比，GSK-3β抑制剂均能显著抑制啮齿动物移植瘤的增殖，并呈剂量依赖关系。移植瘤的组织化学和免疫组织化学分析显示，无论是GSK-3β抑制剂还是GSK-3β抑制剂治疗的小鼠，增殖细胞比例显著减少，癌细胞凋亡率增加，且呈剂量依赖关系。在治疗过程中，啮齿类动物没有观察到任何不良事件或影响，除了罕见的因腹腔注射而导致的致命事故。形态学检查显示，DMSO和GSK-3β抑制剂对啮齿类动物的肺、肝、胰腺、肾、脾和大肠等主要器官没有明显的病理变化。结果表明，GSK-3β抑制剂有望成为一类新型的结肠癌治疗药物。
The authors' recent discovery that glycogen synthase kinase-3 beta (GSK-3 beta) participates in colon cancer cells' survival and proliferation prompted us to investigate whether GSK-3 beta inhibition alters proliferation of colon cancer cells in vivo. Groups of four or five athymic mice (Balb/c, nu/nu) with subcutaneous xenografts of SW480 human colon cancer cells were treated with dimethyl sulfoxide (DMSO) or different doses (1, 2 and 5 mg/kg body weight) of either small-molecule GSK-3 beta inhibitor (SB-216763 and AR-A014418) by intraperitoneal injection three times per week for 5 weeks. Compared with DMSO (a diluent of the GSK-3 beta inhibitors) as a control, either GSK-3 beta inhibitor significantly inhibited proliferation of cancer cell xenografts in the rodents in a dose-dependent manner. Histochemical and immunohistochemical analysis of tumor xenografts demonstrated a significant, dose-dependent decrease in fractions of proliferating cells and an increase in the incidence of apoptosis of cancer cells in mice treated with either GSK-3 beta inhibitor. No adverse events or effects were observed in the rodents during the course of treatment, except for rare lethal accidents due to intraperitoneal injection. Morphological examination showed no apparent pathologic changes in major organs including the lungs, liver, pancreas, kidneys, spleen and large bowel of rodents treated with DMSO and the GSK-3 beta inhibitors. The results indicate that the GSK-3 beta inhibitors would be a novel class of therapeutic agent for colon cancer.