Inhibition of Rho-Associated Kinase 1/2 Attenuates Tumor Growth in Murine Gastric Cancer.
Inhibition of Rho-Associated Kinase 1/2 Attenuates Tumor Growth in Murine Gastric Cancer.
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Rho相关激酶1/2的抑制作用减弱了鼠胃癌的肿瘤生长。
DOI：
10.1016/j.neo.2016.07.002
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发表时间：
2016-08
期刊：
影响因子：
4.8
通讯作者：
Burgermeister, Elke
中科院分区：
文献类型：
--
作者：
Hinsenkamp, Isabel;Schulz, Sandra;Roscher, Mareike;Suhr, Anne-Maria;Meyer, Bjoern;Munteanu, Bogdan;Fuchser, Jens;Schoenberg, Stefan O.;Ebert, Matthias P. A.;Waengler, Bjoern;Hopf, Carsten;Burgermeister, Elke
胃癌（GC）是一种高死亡率的恶性疾病。患者通常在生存预后较差的晚期确诊。因此，迫切需要寻找新的药物靶点和治疗策略。最近，GC亚型的综合分子特征揭示了小GTPase RHOA突变是弥漫性GC的标志。RHOA激活RHOA相关蛋白激酶（ROCK1/2），调节细胞收缩、迁移和生长，因此可能在癌症中发挥作用。然而，到目前为止，抑制rho通路对胃癌的治疗效果尚未得到证实。ROCK1/2抑制剂1-（5-异喹啉磺酰）-homopiperazine （HA-1077，法舒地尔）被批准用于脑血管出血患者。因此，我们在临床前胃癌模型中研究法舒地尔（ig，每天10 mg/kg，每周4次，4周）是否抑制肿瘤生长。法舒地尔可引起人胃癌细胞死亡，并可减小CEA424-SV40 TAg转基因小鼠胃内肿瘤大小。小动物PET/CT证实临床前疗效。质谱成像鉴定出一种可翻译的小鼠GC生物标志物，表明该药物在胃肿瘤组织中的原位分布迅速但不完全。与正常非恶性胃组织相比，肿瘤小鼠胃中的RHOA表达增加，法舒地尔在体内和体外人胃癌细胞中（自动）降低了THR249位点ROCK2的磷酸化。总之，我们的数据表明，抑制rho通路可能是治疗胃癌的一种新策略，未来ROCK抑制剂在肿瘤组织中的分布可能会进一步提高疗效。
Gastric cancer (GC) remains a malignant disease with high mortality. Patients are frequently diagnosed in advanced stages where survival prognosis is poor. Thus, there is high medical need to find novel drug targets and treatment strategies. Recently, the comprehensive molecular characterization of GC subtypes revealed mutations in the small GTPase RHOA as a hallmark of diffuse-type GC. RHOA activates RHO-associated protein kinases (ROCK1/2) which regulate cell contractility, migration and growth and thus may play a role in cancer. However, therapeutic benefit of RHO-pathway inhibition in GC has not been shown so far. The ROCK1/2 inhibitor 1-(5-isoquinoline sulfonyl)-homopiperazine (HA-1077, fasudil) is approved for cerebrovascular bleeding in patients. We therefore investigated whether fasudil (i.p., 10 mg/kg per day, 4 times per week, 4 weeks) inhibits tumor growth in a preclinical model of GC. Fasudil evoked cell death in human GC cells and reduced the tumor size in the stomach of CEA424-SV40 TAg transgenic mice. Small animal PET/CT confirmed preclinical efficacy. Mass spectrometry imaging identified a translatable biomarker for mouse GC and suggested rapid but incomplete in situ distribution of the drug to gastric tumor tissue. RHOA expression was increased in the neoplastic murine stomach compared with normal non-malignant gastric tissue, and fasudil reduced (auto) phosphorylation of ROCK2 at THR249 in vivo and in human GC cells in vitro. In sum, our data suggest that RHO-pathway inhibition may constitute a novel strategy for treatment of GC and that enhanced distribution of future ROCK inhibitors into tumor tissue may further improve efficacy.
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影响因子：
7.4
作者：
Fueloep, Annabelle;Porada, Martina B.;Hopf, Carsten
通讯作者：
Hopf, Carsten
影响因子：
5.3
作者：
Burgermeister, Elke;Friedrich, Teresa;Ebert, Matthias P. A.
通讯作者：
Ebert, Matthias P. A.
影响因子：
158.5
作者：
Ebert, Matthias P. A.;Taenzer, Marc;Schmid, Roland M.
通讯作者：
Schmid, Roland M.
影响因子：
11.2
作者：
Burgermeister, Elke;Xing, Xiangbin;Ebert, Matthias P. A.
通讯作者：
Ebert, Matthias P. A.
影响因子：
4.1
作者：
Doran, JD;Liu, X;Fox, T
通讯作者：
Fox, T