Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells.
Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells.
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伊曲康唑通过抑制胃癌细胞中的 Hedgehog 信号传导诱导细胞凋亡和细胞周期停滞
DOI：
10.1186/s13046-017-0526-0
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发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Xiong H
中科院分区：
文献类型：
--
作者：
Hu Q;Hou YC;Huang J;Fang JY;Xiong H
伊曲康唑已被证明对多种人类癌症有效。本研究评估了伊曲康唑对Hedgehog（Hh）途径和人胃癌细胞增殖的影响。采用CCK-8法和集落形成实验观察伊曲康唑对胃癌细胞增殖的影响。通过逆转录聚合酶链反应、免疫印迹和双荧光素酶试验评估伊曲康唑处理后胃癌细胞中Hh信号成分的表达。采用裸鼠移植瘤模型观察伊曲康唑对胃癌细胞增殖的抑制作用。伊曲康唑能显著抑制胃癌细胞的增殖。当与5-FU联合使用时，伊曲康唑显著降低癌细胞的增殖率。伊曲康唑可调节胃癌细胞G1-S期转换，诱导胃癌细胞凋亡。人类胃癌样本中Hh信号异常激活。体外研究表明，伊曲康唑治疗后，胶质瘤相关锌指转录因子1（Gli 1）的表达在转录和翻译水平上均降低。双荧光素酶试验也表明伊曲康唑能抑制Gli 1的转录。体内研究表明，单药口服伊曲康唑可抑制异种移植物的生长，伊曲康唑可显著增强化疗药物5-FU的抗肿瘤疗效。胃肿瘤中Hh信号被激活，伊曲康唑可通过抑制Gli 1表达抑制胃癌细胞生长。
Itraconazole has been proved therapeutically effective against a variety of human cancers. This study assessed the effect of itraconazole on the Hedgehog (Hh) pathway and proliferation of human gastric cancer cells. CCK-8 assay and colony formation assay were used to assess the effects of itraconazole on proliferation of gastric cancer cells. The expression of Hh signaling components in gastric cancer cells treated with itraconazole was evaluated by reverse-transcription polymerase chain reaction, immunoblotting and dual luciferase assay. Tumor xenograft models were used to assess the inhibitory effect of itraconazole on the proliferation of gastric cancer cells in vivo. Itraconazole could remarkably inhibit the proliferation of gastric cancer cells. When in combination with 5-FU, itraconazole significantly reduced the proliferation rate of cancer cells. Furthermore, itraconazole could regulate the G1-S transition and induce apoptosis of gastric cancer cells. Hh signaling was abnormally activated in human gastric cancer samples. In vitro, studies showed that the expression of glioma-associated zinc finger transcription factor 1 (Gli1) was decreased at both transcriptional and translational levels after treatment with itraconazole. Dual luciferase assay also indicated that itraconazole could inhibit the transcription of Gli1. In vivo studies demonstrated that monotherapy with itraconazole by oral administration could inhibit the growth of xenografts, and that itraconazole could significantly enhance the antitumor efficacy of the chemotherapeutic agent 5-FU. Hh signaling is activated in gastric tumor and itraconazole can inhibit the growth of gastric cancer cells by inhibiting Gli1 expression.