Oridonin inhibits mTOR signaling and the growth of lung cancer tumors
Oridonin inhibits mTOR signaling and the growth of lung cancer tumors
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DOI：
10.1097/cad.0000000000000154
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发表时间：
2014-11
影响因子：
2.3
通讯作者：
Yan-Yan Wang-Yan;Yan Lv;Lu Lu-Lu;L. Cai
中科院分区：
文献类型：
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作者：
Yan-Yan Wang-Yan;Yan Lv;Lu Lu-Lu;L. Cai
冬凌草甲素是从冬凌草中分离得到的一种活性二萜类化合物，已被广泛用于治疗各种类型的癌症。已经显示，冬凌草甲素在体外肺癌细胞系中产生抗增殖作用。然而，冬凌草甲素对肺癌细胞移植瘤小鼠的抗肿瘤作用尚不清楚。本研究的目的是探讨冬凌草甲素的体内抗肿瘤活性及其分子机制。将人A549和NCI-H292非小细胞肺癌细胞株转移至裸鼠体内建立异种移植瘤模型。结果表明，冬凌草甲素（10、20、40 mg/kg，腹腔注射）治疗A549和NCI-H292荷瘤小鼠28 d后，肿瘤体积明显缩小，肿瘤生长受到明显抑制。同时，冬凌草甲素还可通过增加dUTP缺口末端标记阳性细胞数和Bax/Bcl-2比值促进移植瘤细胞凋亡。此外，长期给予冬凌草甲素通过降低p-mTOR和p-p70 s6 k水平抑制哺乳动物雷帕霉素靶蛋白（mTORC 1）活性，表明给予冬凌草甲素引发的细胞凋亡增加与mTORC 1活性下调相关。此外，雷帕霉素（2 mg/kg，腹腔注射）抑制mTORC 1增强了冬凌草甲素在小鼠异种移植模型中的抗癌活性。这些发现表明，用冬凌草甲素处理通过抑制mTORC 1功能诱导凋亡反应而表现出抗肿瘤作用。我们的研究结果还提出了mTORC 1的抑制可能是增加用冬凌草甲素治疗的肺癌患者的治疗结果的有效靶点。
Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been widely used for treatment of various types of cancer. It has been shown that oridonin produced an antiproliferative effect in a lung cancer cell line in vitro. However, the antitumor effects of oridonin in lung cancer cells xenograft mice were poorly understood. The aim of the current study was to investigate the antitumor activity of oridonin in vivo and the molecular mechanisms mediating this antitumor efficacy. The human A549 and NCI-H292 non-small cell lung cancer cell lines were transferred to nude mice for the establishment of xenograft models. The results showed that oridonin (10, 20, 40 mg/kg, intraperitoneally) treatment for 28 days significantly decreased tumor volume and induced tumor growth inhibition in both A549 and NCI-H292 xenograft mice. Furthermore, oridonin promoted apoptosis by increasing terminal dUTP nick end labeling-positive cells as well as the ratio of Bax/Bcl-2 in xenograft mice. In addition, chronic oridonin administration inhibited mammalian target of rapamycin (mTORC1) activity by reduction of p-mTOR and p-p70s6k levels, suggesting that the increased apoptosis triggered by oridonin administration was associated with the downregulation of mTORC1 activity. Moreover, inhibition of mTORC1 by rapamycin (2 mg/kg, intraperitoneally) enhanced the anticancer activity of oridonin in mice xenograft models. These findings indicate that treatment with oridonin exhibited antitumor actions through induction of apoptotic response by inhibition of mTORC1 function. Our results also proposed the potential that inhibition of mTORC1 might be an effective target for increasing the therapeutic outcome in lung cancer patients treated with oridonin.