Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo.
Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo.
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DT-13与托泊替康协同组合通过肌球蛋白IIA诱导的体外和体内egf受体内吞作用抑制人胃癌
DOI：
10.18632/oncotarget.8843
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发表时间：
2016-05-31
期刊：
影响因子：
--
通讯作者：
Sun L
中科院分区：
文献类型：
--
作者：
Yu XW;Lin S;Du HZ;Zhao RP;Feng SY;Yu BY;Zhang LY;Li RM;Qian CM;Luo XJ;Yuan ST;Sun L
与单一疗法相比，联合疗法对许多癌症具有更高的成功率。拓扑替康（Topotecan，TPT）的毒性和潜在的耐药性限制了其对胃癌的治疗。我们发现，来自矮麦冬的皂苷单体13（DT-13），执行抗转移和抗血管生成作用，与TPT的组合协同诱导具有高EGF受体（EGFR）表达的GC中的细胞凋亡细胞毒性，这依赖于DT-13诱导的EGFR内吞作用。与TPT，DT-13通过肌球蛋白IIA诱导和Src/小窝蛋白-1（Cav-1）诱导的EGFR内吞促进EGFR泛素介导的降解;抑制EGFR下游信号传导，然后增加促凋亡作用。此外，DT-13和TPT在EGFR高表达的GC中的协同促凋亡功效被NM II抑制剂（-）-blebbistatin和MYH-9 shRNA消除。DT-13与TPT的联合治疗显示出比它们单独作用更强的体内抗肿瘤作用。此外，联合治疗的结果显示，选择性上调促凋亡活性在TUNEL法和切割的caspase-3和NM IIA在免疫组化分析，而特异性下调p-细胞外调节激酶1/2（p-ERK 1/2），EGFR和Cav-1在免疫组化分析。总的来说，由于该方案可能具有高敏感性，这些发现对EGFR高表达的肿瘤患者具有显著的临床意义。
Combination therapy has a higher success rate for many cancers compared to mono-therapy. The treatment of Topotecan (TPT) on gastric cancer (GC) is limited by its toxicity and the potential drug resistance. We found that the combination of the saponin monomer 13 from the dwarf lilyturf tuber (DT-13), performing anti-metastasis and anti-angiogenesis effects, with TPT synergistically induced apoptotic cytotoxicity in GCs with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR. With TPT, DT-13 promoted EGFR ubiquitin--mediated degradation through myosin IIA-induced and Src/ caveolin-1 (Cav-1)-induced endocytosis of EGFR; inhibited EGFR downstream signalling and then increased the pro-apoptotic effects. Moreover, the synergistic pro-apoptotic efficacy of DT-13 and TPT in GCs with high EGFR expression was eliminated by both the NM II inhibitor (−)-blebbistatin and MYH-9 shRNA. The combination therapy of DT-13 with TPT showed stronger anti-tumour effects in vivo compared with their individual effects. Moreover, the results of combination therapy revealed selective upregulation of pro-apoptotic activity in TUNEL assays and cleaved caspase-3 and NM IIA in immunohischemical analysis; while specific downregulation of p-extracellular regulated kinase 1/2 (p-ERK1/2), EGFR and Cav-1 in immunohischemical analysis. Collectively, these findings have significant clinical implications for patients with tumours harbouring high EGFR expression due to the possible high sensitivity of this regimen.
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影响因子：
4.1
作者：
Park, Inju;Han, Cecil;Cho, Chunghee
通讯作者：
Cho, Chunghee
影响因子：
11.5
作者：
Okabe, Takafumi;Okamoto, Isamu;Nakagawa, Kazuhiko
通讯作者：
Nakagawa, Kazuhiko
DOI：
10.1038/nrm2786
发表时间：
2009-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Thomas S;Overdevest JB;Nitz MD;Williams PD;Owens CR;Sanchez-Carbayo M;Frierson HF;Schwartz MA;Theodorescu D
通讯作者：
Theodorescu D
影响因子：
11.2
作者：
Joshi, Bharat;Strugnell, Scott S.;Nabi, Ivan R.
通讯作者：
Nabi, Ivan R.