The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis.
The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis.
复制标题
紫草素诱导RIP1和RIP3依赖性坏死性凋亡对骨肉瘤的抗肿瘤作用
DOI：
10.1186/1471-2407-13-580
复制
发表时间：
2013-12-06
期刊：
影响因子：
3.8
通讯作者：
Cai Z
中科院分区：
文献类型：
--
作者：
Fu Z;Deng B;Liao Y;Shan L;Yin F;Wang Z;Zeng H;Zuo D;Hua Y;Cai Z
骨肉瘤是最常见的原发性恶性骨肿瘤，以肺转移著称。紫草素是一种从中草药中提取的有效成分，在某些癌症中被证明具有诱导坏死性凋亡的作用。MTT法检测细胞存活率。流式细胞仪分析细胞周期和细胞死亡。Western blot检测RIP 1、RIP 3、caspase-3、caspase-6和PARP的表达水平。采用胫骨原发性和肺转移性骨肉瘤模型评价紫草素的体内抗肿瘤作用。紫草素处理后细胞存活率呈剂量和时间依赖性下降。紫草素对细胞周期无明显影响。特异性坏死凋亡抑制剂necrostatin-1可显著减轻紫草素诱导的细胞死亡，而一般性caspase抑制剂Z-VAD-FMK则不能减轻紫草素诱导的细胞死亡。流式细胞仪检测到经Nec-1预处理后，K7细胞中紫草素引起的坏死细胞数减少。经紫草素处理8 h后，K7和U2 OS细胞中RIP 1和RIP 3的表达水平升高，而caspase-3、caspase-6和PARP均未被激活。紫草素治疗组的原发肿瘤和肺转移灶明显缩小。紫草素可提高原发肿瘤组织中RIP 1和RIP 3的蛋白水平。肺转移模型组总生存期较对照组延长（P < 0.001）。紫草素对原发性和转移性骨肉瘤具有迅速而深远的抗肿瘤作用，可能是通过诱导RIP 1和RIP 3依赖的坏死性凋亡。紫草素有望成为治疗原发性和转移性骨肉瘤的有效药物。
Osteosarcoma is the most frequent primary malignant bone tumor, notorious for its lung metastasis. Shikonin, an effective constituent extracted from Chinese medicinal herb, was demonstrated to induce necroptosis in some cancers. MTT assay was performed to detect cell survival rate in vitro. Flow cytometry was used to analyze cell cycle and cell death. Western blot was performed to determine the expression levels of RIP1, RIP3, caspase-3, caspase-6 and PARP. The tibial primary and lung metastatic osteosarcoma models were used to evaluate the anti-tumor effect of shikonin in vivo. The cell survival rate was decreased in a dose and time dependent manner when treated with shikonin. No major change in cell cycle was observed after shikonin treatment. The cell death induced by shikonin could be mostly rescued by specific necroptosis inhibitor necrostatin-1, but not by general caspase inhibitor Z-VAD-FMK. The number of necrotic cells caused by shikonin was decreased after being pretreated with Nec-1 detected by flow cytometry in K7 cells. After 8-hour treatment of shikonin, the expression levels of RIP1 and RIP3 were increased while caspase-3, caspase-6 and PARP were not activated in K7 and U2OS cells determined by Western blot. Size of primary tumor and lung metastasis in shikonin treated group were significantly reduced. The protein levels of RIP1 and RIP3 in primary tumor tissues were increased by shikonin. The overall survival of lung metastatic models was longer compared with control group (p < 0.001). Shikonin had prompt but profound anti-tumor effect on both primary and metastatic osteosarcoma, probably by inducing RIP1 and RIP3 dependent necroptosis. Shikonin would be a potential anti-tumor agent on the treatment of primary and metastatic osteosarcoma.
登录
查看更多内容
影响因子：
3.4
作者：
Leow, Pay-Chin;Tian, Quan;Ee, Pui-Lai Rachel
通讯作者：
Ee, Pui-Lai Rachel
影响因子：
4.3
作者：
Park, Seungyeon;Shin, Heesuk;Cho, Youngsik
通讯作者：
Cho, Youngsik
影响因子：
64.5
作者：
Li J;McQuade T;Siemer AB;Napetschnig J;Moriwaki K;Hsiao YS;Damko E;Moquin D;Walz T;McDermott A;Chan FK;Wu H
通讯作者：
Wu H
影响因子：
3.7
作者：
Huang C;Luo Y;Zhao J;Yang F;Zhao H;Fan W;Ge P
通讯作者：
Ge P
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK