姜黄素纳米粒(NanoCurcTM)联合索拉非尼对肝细胞癌(HCC)的协同抑制作

 目的 探讨姜黄素纳米粒(NanoCurcTM,NC) 单药或联合索拉非尼对人肝细胞癌(hepatocellular carcinoma,HCC)的作用。方法 采用体外细胞增殖检测试剂盒(CCK-8)、体外划痕试验和Transwell侵袭试验法检测NC和/或索拉非尼对肝癌细胞株MHCCLM3增殖、迁移、侵袭能力的影响;应用流式细胞术分析其对细胞凋亡的作用。建立裸鼠MHCCLM3原位移植模型并观察NC和/或索拉非尼对肿瘤大小和肺转移率的影响。应用RT PCR、ELISA、Western blot法检测基质金属蛋白酶 9 (matrix metalloproteinase 9,MMP-9)、基质金属蛋白酶抑制剂-1 （tissue inhibitor of metalloproteinase 1,TIMP-1)、细胞外信号调节激酶1/2 (ERK1/2) mRNA或相应蛋白表达变化;并测定ERK1/2的磷酸化变化。结果 NC与索拉非尼联合应用可显著抑制HCC体外增殖和侵袭能力(P<0.01),抑制体内肿瘤生长和肺转移(P<0.01)。单独应用NC和索拉非尼时肺转移率分别为50.0%和66.7%,两者联合用药时则显著降低至16.7%。两药联合应用可协同抑制ERK磷酸化,从而下调MMP 9的表达。结论  NC联合索拉非尼可通过协同诱导细胞凋亡、抑制MMP-9的表达而抑制肝癌生长和转移。

Synergistic antitumor effects of polymeric nanoparticle formulation of curcumin (NanoCurcTM) combined with sorafenib in human hepatocellular carcinoma (HCC)

Objective  To investigate the effect of polymeric nanoparticle formulation of curcumin (NanoCurcTM,NC) alone and in combination with sorafenib using in vitro and in vivo models of human hepatocellular carcinoma (HCC).Methods  The activity of NC alone and in combination with sorafenib on HCC cell lines (MHCCLM3) was determined by CCK8,wound healing and modified Boyden chamber assays.Apoptosis of cells was detected by flow cytometry.Primary HCC tumor growth and metastasis were examined in vivo using orthotopic HCC xenografts in nude mice.RT-PCR,Western blot and ELISA were used to determine the expressions of matrix metalloproteinase-9 (MMP-9),tissue inhibitor of metalloproteinase 1 (TIMP-1),extracellular sinal regulated kinase 1/2 (ERK1/2) and phosphorylated ERK 1/2 (p ERK1/2).Results  NC combined with sorafenib significantly inhibited the proliferation and invasion of MHCCLM3 cells in vitro (P<0.01),also drastically suppressed primary tumor growth and lung metastases in vivo (P<0.01).Lung metastatic rate was 50.0% and 66.7% when NC and sorafenib was used alone separately,and descended to 16.7% when NC and sorafenib were combined.NC combined with sorafenib could synergistically down-regulate the expression of MMP-9 via inhibiting p ERK1/2 expression.Conclusions  Combination of NC and sorafenib showed synergistic inhibition effects on tumor growth and metastases by inducing cell apoptosis and inhibiting the expression of MMP-9.