Sorafenib and triptolide as combination therapy for hepatocellular carcinoma
Sorafenib and triptolide as combination therapy for hepatocellular carcinoma
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DOI：
10.1016/j.surg.2014.04.055
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发表时间：
2014-08-01
期刊：
影响因子：
3.8
通讯作者：
Jensen, Eric H.
中科院分区：
文献类型：
--
作者：
Alsaied, Osama A.;Sangwan, Veena;Jensen, Eric H.
导论.索拉非尼是美国食品和药物管理局批准的唯一一种用于转移性肝细胞癌（HCC）的药物。雷公藤内酯醇是一种二萜三环氧化物，在多种肿瘤细胞类型中表现出抗肿瘤特性。在这项研究中，我们研究了这些药物及其组合对肝癌的体外和体内模型的影响。HuH-7和PLC/PRF/5细胞用雷公藤甲素（50 nM）、索拉非尼（1.25或2.5 μ M）或两者的组合处理。进行细胞活力测定（CCK-8）、半胱天冬酶3&7活化和核因子KB测定。在体内研究中，将40只小鼠皮下植入HuH 7肿瘤，并分成四个治疗组（n =10）;盐水对照组、索拉非尼10 mg/kg PO每日一次（S）、明尼利特（雷公藤内酯醇的前药）0.21 mg/kg腹膜内每日一次（M）和两者的组合（C）。每周评估肿瘤体积。雷公藤甲素和索拉非尼联合用药在诱导细胞凋亡方面上级优于单独用药。降低存活率，而雷公藤内酯醇单独足以降低核因子κ B活性。治疗2周后，肿瘤生长抑制率为S = 59%，M = 84%和C = 93%，而对照动物的肿瘤体积增加了9倍。当交叉到联合治疗时，对照小鼠肿瘤生长体积在接下来的4周内达到稳定。索拉非尼和雷公藤甲素的组合在体外增加细胞死亡和凋亡方面上级单一药物治疗。联合索拉非尼与明尼来抑制肿瘤生长的效果比单药治疗更好。重要的是，体内联合治疗允许使用较低剂量的索拉非尼（10 mg/kg），其小于HCC患者目前处方剂量的10%。因此，联合治疗可能在HCC的管理中具有转化潜力。
Introduction. Sorafenib is the only drug approved by the Food and Drug Administration for metastatic hepatocellular carcinoma (HCC). Triptolide, a diterpene triepoxide, exhibits antineoplastic properties in multiple tumor cell types. In this study, we examined the effects of these agents and their combination on HCC in vitro and in vivo models.Methods. HuH-7 and PLC/PRF/5 cells were treated with triptolide (50 nM), sorafenib (1.25 or 2.5 mu M), or a combination of both. Cell viability assay (CCK-8), caspase 3&7 activation, and nuclear factor KB assays were performed. Form vivo studies, 40 mice were implanted with subcutaneous HuH7 tumors and divided into four treatment groups (n =10); saline control, sorafenib 10 mg/kg PO daily (S), Minnelide (a prodrug of triptolide) 0.21 mg/kg intraperitoneally7 daily (M), and combination of both (C). Tumor volumes were assessed weekly.Results. The combination of triptolide and sorafenib was superior to either drug alone in inducing apoptosis and. decreasing viability, whereas triptolide alone was sufficient to decrease nuclear factor kappa B activity. After 2 weeks of treatment, tumor growth inhibition rates were S = 59%, M = 84%, and C = 93%, whereas tumor volumes in control animals increased by 9-fold. When crossed over to combination treatment, control mice tumor growth volumes plateaued over the following 4 weeks.Conclusion. The combination of sorafenib and triptolide is superior to single drug treatment in increasing cell death and apoptosis in vitro. Combining sorafenib with Minnelide inhibited tumor growth with greater efficacy than single-agent treatments. Importantly, in vivo combination treatment allowed for using a lesser dose of sorafenib (10 mg/kg), which is less than 10% of currently prescribed dose for HCC patients. Therefore, combination treatment could have translational potential in the management of HCC.