目的:研究活血化瘀治法(the medicine group of promoting blood circulation and removing stasis,PBCRS)对7,12-二甲基苯蒽[7,12-dimethylbenz(a) anthracene,DMBA]诱发性大鼠乳腺癌的抑制作用,及运用转录组测序技术(RNA sequencing,R...目的:研究活血化瘀治法(the medicine group of promoting blood circulation and removing stasis,PBCRS)对7,12-二甲基苯蒽[7,12-dimethylbenz(a) anthracene,DMBA]诱发性大鼠乳腺癌的抑制作用,及运用转录组测序技术(RNA sequencing,RNA-seq)和信号网络分析(ingenuity pathway analysis,IPA)软件筛选关键基因和验证。方法:将96只SD大鼠随机分为空白组,DMBA模型组,枸橼酸他莫昔芬(Tamoxifen,TAM)组(1.9 mg·kg^(-1)·d-1),PBCRS高、中、低剂量组(12.96,6.48,3.24 g·kg^(-1)·d-1)。药物干预1周后,除空白组外,采用DMBA诱导大鼠乳腺癌模型(灌服2次,间隔1周,剂量100 mg·kg^(-1))。给药10周后,观察大鼠荷瘤重、荷瘤体积变化,用总RNA提取试剂盒提取总RNA,从DMBA模型组和PBCRS中剂量组各取3个RNA样品进行基因检测,筛选出关键差异基因,用实时荧光定量PCR(Real-time PCR)验证关键基因。结果:与DMBA模型组比较,PBCRS中剂量组荷瘤重和荷瘤体积均明显降低(P<0.05),PBCRS高、低剂量组荷瘤重和荷瘤体积虽有降低,但与DMBA模型组比较差异均无统计学意义;基于RNA-seq技术及IPA分析软件筛选出果糖1,6二磷酸酶1 (fructose-1,6-bisphosphatase1,FBP1),浦肯野细胞蛋白4(purkinje cell protein 4,PCP4),肌红蛋白(myoglobin,MB) 3个关键基因;与DMBA模型组比较,PBCRS高、中剂量组FBP1 mRNA表达均明显升高(P<0.05),PBCRS低剂量组FBP1 mRNA表达升高,但差异无统计学意义,PBCRS高、中、低剂量组PCP4 mRNA的表达增高,但无统计学差异,PBCRS低剂量组MB mRNA的表达虽降低,差异无统计学意义。结论:PBCRS可能通过干预乳腺癌组织中FBP1的表达,抑制乳腺癌的发生。展开更多
Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(C...Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis fields(CoMSIA)was implemented on 52 dual CDK4/6 inhibitors.As a result,we obtained a pretty good 3D-QSAR model,which is CoMFACDK4 with q2 to be 0.543 and r^(2) to be 0.967;CoMSIACDK4 with q2 being 0.518 and r^(2) being 0.937;CoMFACDK6 with q2 to be 0.624 and r^(2) to be 0.984;CoMSIACDK6 with q2 being 0.584 and r^(2) being 0.975.Molecular docking confirmed the important residues for interactions.Molecular dynamics simulation further confirmed binding affinity with key residues of protein,such as Lys22,Lys35,Val96 for CDK4 and Lys43,His100,Val101 for CDK6 at the active sites.Then these results offered new directions to explore new inhibitors of CDK4/6.Finally,we designed 10 novel compounds with promising expected activity and ADME/T properties,and provided referable synthetic routes.展开更多
基金supported by the key project of Chongqing Natural Science Foundation (cstc2015jcyj BX0080)
文摘Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis fields(CoMSIA)was implemented on 52 dual CDK4/6 inhibitors.As a result,we obtained a pretty good 3D-QSAR model,which is CoMFACDK4 with q2 to be 0.543 and r^(2) to be 0.967;CoMSIACDK4 with q2 being 0.518 and r^(2) being 0.937;CoMFACDK6 with q2 to be 0.624 and r^(2) to be 0.984;CoMSIACDK6 with q2 being 0.584 and r^(2) being 0.975.Molecular docking confirmed the important residues for interactions.Molecular dynamics simulation further confirmed binding affinity with key residues of protein,such as Lys22,Lys35,Val96 for CDK4 and Lys43,His100,Val101 for CDK6 at the active sites.Then these results offered new directions to explore new inhibitors of CDK4/6.Finally,we designed 10 novel compounds with promising expected activity and ADME/T properties,and provided referable synthetic routes.
