CC-5079: a small molecule with MKP1, antiangiogenic, and antitumor activity.
CC-5079: a small molecule with MKP1, antiangiogenic, and antitumor activity.
复制标题
DOI：
10.1016/j.jss.2009.01.031
复制
发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Huan N Vu;Walter Miller;Sarah O'Connor;Mei He;P. Schafer;F. Payvandi;G. Muller;D. Stirling;S. Libutti
中科院分区：
文献类型：
--
作者：
Huan N Vu;Walter Miller;Sarah O'Connor;Mei He;P. Schafer;F. Payvandi;G. Muller;D. Stirling;S. Libutti
[目的]评价微管蛋白聚合和磷酸二酯酶-4活性的小分子抑制剂CC-5079的抗血管生成和抗肿瘤活性。通过增殖、迁移和侵袭实验评价CC-5079对人脐静脉内皮细胞(HUVECs)、成纤维细胞和MC38的体外活性。其次，通过鸡胚绒毛尿囊膜(CAM)、大鼠主动脉环实验和体内直接血管生成实验(DIVAA)观察CC-5079对微血管形成的影响。第三，检测CC-5079对C57BL/6小鼠MC38肿瘤的治疗作用。结果0.1μM浓度的CC-5079显著抑制人脐静脉内皮细胞、成纤维细胞和MC38的增殖和迁移(P均<0.001)。在0.1μM浓度下，CC-5079也能抑制人脐静脉内皮细胞的侵袭，但不能抑制成纤维细胞的侵袭。在CAM和大鼠主动脉环实验中，0.1μM的CC-5079抑制微血管形成(P<；0.05)。在DIVAA中，CC-5079 1 mg/kg/d连续给药抑制微血管形成(P<；0.05)。腹腔注射CC-5079耐受性良好，100 mg/kg/d可抑制MC38的生长(P<；0.01)。通过qRT-PCR检测，CC-5079可刺激人脐静脉内皮细胞和成纤维细胞mkp1的表达。结论CC-5079具有刺激Mkp1、抗血管生成和抗肿瘤作用。
INTRODUCTIONCC-5079, a small molecule inhibitor of tubulin polymerization and phosphodiesterase-4 activity, was evaluated for antiangiogenic and antitumor activities.MATERIALS AND METHODSFirst, CC-5079 in vitro activity on human umbilical vein endothelial cells (HUVECs), fibroblasts, and MC38 were evaluated by proliferation, migration, and invasion assays. Second, CC-5079 effect on microvessel formation was evaluated ex vivo by chick chorioallantoic membrane (CAM), rat aortic rings assays, and with directed in vivo angiogenesis assay (DIVAA). Third, CC-5079 antitumor effect was determined in treatment of C57BL/6 mice with MC38 tumors. Finally, CC-5079 modulation of MKP1 in HUVECs, human fibroblast, and MC38 were determined by RNA isolation for qRT-PCR.RESULTSAt the 0.1 μM concentration CC-5079 significantly inhibited HUVEC, fibroblast, and MC38 proliferation and migration (all P < 0.001). At the 0.1 μM concentration, CC-5079 also inhibited HUVEC invasion (P < 0.05) but not fibroblast. In the CAM and rat aortic ring assays, CC-5079 at 0.1 μM inhibited microvessel formation (P < 0.05). By DIVAA, CC-5079 at 1 mg/kg/d continuous delivered inhibited microvessel formation (P < 0.05). Intraperitoneal CC-5079 was well tolerated and inhibited the growth of subcutaneous MC38 at 100 mg/kg/d (P < 0.01). By qRT-PCR, CC-5079 stimulated MKP1 expression in HUVEC and fibroblast.CONCLUSIONCC-5079 demonstrated stimulation of MKP1, antiangiogenic, and antitumor properties.