PI3Kγ抑制剂AS605240抗小鼠乳腺癌实验研究
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摘要
目的探讨PI3Kγ抑制剂AS605240抗小鼠乳腺癌的效果与相关机制。方法选择BALC小鼠30只,通过皮下注射4T1小鼠乳腺癌细胞株建立乳腺癌小鼠模型,肿瘤形成后30只BALC小鼠分为对照组、空载组与AS605240组各10只,对照组口服与AS605240组等体积DMSO;空载组口服Ad-vector、DMSO溶液各10μL;AS605240组口服AS605240溶液10μL,观察、记录肿瘤组织变化情况并进行蛋白杂交分析。结果治疗后各组BALC小鼠均未死亡,AS605240组肿瘤体积为(378.41±56.11)mm3,小于空载组(2 533.42±123.33)mm3和对照组(2 440.42±186.48)mm3,差异有统计学意义(P <0.05)。治疗后AS605240组的细胞凋亡指数为(22.81±3.12)%,高于空载组与对照组的(3.79±1.33)%和(3.29±1.92)%,差异有统计学意义(P<0.05)。蛋白质印迹检测显示,与空载组、对照组对比,治疗后AS605240组肿瘤组织标本的PCNA、CyclinD1、Caspase-3蛋白表达量降低,差异有统计学意义(P<0.05)。结论 PI3Kγ抑制剂AS605240在体内具有一定的抑制小鼠乳腺癌增殖的作用,可促使肿瘤组织细胞凋亡,其作用机制可能与调节PCNA、CyclinD1、Caspase-3表达有关。
Objective To study the anti-breast cancer effect of the PI3 Kγinhibitor AS605240 in mice and its mechanism.Methods A total of 30 BALB mice were selected and used to construct the model mice with breast cancer by subcutaneous injection of 4 T1 mice breast cancer cell strains.After the tumor formation,those mice were divided the control group,and AS605240 group with 10 mice in each group.The control group was administered orally with 10 oDMSO solution,the empty vector group was treated orally with 10μL Ad-vector solution and 10μL DMSO solution,and the AS605240 group was given orally 10μL AS605240 solution.The changes of tumor tissues were observed and recorded and the protein blot analysis was carried out.Results There were no dead mice in each group after treatment.The tumor volume were of the AS605240 group was(378.41±56.11)mm3 and it was significantly less than the tumor volumes of the empty vector group and the control group which were(2533.42±123.33)mm3 and(2440.42±186.48)mm3(P<0.05)respectively.The apoptosis index of the AS605240 group was(22.81+3.12)% and it was significantly higher than the apoptosis indexes of the empty vector group and the control group which were(3.79+1.33)% and(3.29 +1.92)% respectively(P<0.05).The results of western blot analysis showed that the protein expression levels of PCNA,CyclinD1 and Caspase-3 in the AS605240 group were significantly lower than those in the empty vector group and the control group after treatment(P<0.05).Conclusion The PI3 Kγinhibitor AS605240 has a certain inhibitory effect in vivo on the proliferation of breast cancer in mice by promoting the apoptosis of tumor cells and its mechanism may be related with the expression regulation of PCNA,CyclinD1 and Caspase-3.
Objective To study the anti-breast cancer effect of the PI3 Kγinhibitor AS605240 in mice and its mechanism.Methods A total of 30 BALB mice were selected and used to construct the model mice with breast cancer by subcutaneous injection of 4 T1 mice breast cancer cell strains.After the tumor formation,those mice were divided the control group,and AS605240 group with 10 mice in each group.The control group was administered orally with 10 oDMSO solution,the empty vector group was treated orally with 10μL Ad-vector solution and 10μL DMSO solution,and the AS605240 group was given orally 10μL AS605240 solution.The changes of tumor tissues were observed and recorded and the protein blot analysis was carried out.Results There were no dead mice in each group after treatment.The tumor volume were of the AS605240 group was(378.41±56.11)mm3 and it was significantly less than the tumor volumes of the empty vector group and the control group which were(2533.42±123.33)mm3 and(2440.42±186.48)mm3(P<0.05)respectively.The apoptosis index of the AS605240 group was(22.81+3.12)% and it was significantly higher than the apoptosis indexes of the empty vector group and the control group which were(3.79+1.33)% and(3.29 +1.92)% respectively(P<0.05).The results of western blot analysis showed that the protein expression levels of PCNA,CyclinD1 and Caspase-3 in the AS605240 group were significantly lower than those in the empty vector group and the control group after treatment(P<0.05).Conclusion The PI3 Kγinhibitor AS605240 has a certain inhibitory effect in vivo on the proliferation of breast cancer in mice by promoting the apoptosis of tumor cells and its mechanism may be related with the expression regulation of PCNA,CyclinD1 and Caspase-3.
引文
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[16]潘承欣,崔仁忠,吴绮鋆,等.曲妥珠单抗联合NSC 74859对曲妥珠耐药的乳腺癌细胞的抑制作用研究[J].现代生物医学进展,2016,16(7):1253-1256.
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[18]陈军,赵文晖,刘玲玲,等.异丙酚通过激活PI3K/Akt信号通路抑制癌细胞转移[J].西安交通大学学报(医学版),2016,37(2):226-229.
[19]袁翠堂,丁罡,廖志军,等.大鼠乳腺癌骨转移模型中PI3K/Akt信号通路参与诱导疼痛[J].实用癌症杂志,2016,31(3):349-352,358.
[2]Hu T,Zhou R,Zhao Y X,et al.Integrinα6/Akt/Erk signaling is essential for human breast cancer resistance to radiotherapy[J].Sci Rep,2016,6:33376.
[3]熊晶,喻志华,瞿智玲,等.RNA干扰MDM2下调人乳腺癌细胞中VEGF的合成并抑制肿瘤血管的生成[J].肿瘤防治研究,2016,43(6):473-478.
[4]Le X N,Antony R,Razavi P,et al.Systematic functional characterization of resistance to PI3K inhibition in breast cancer[J].Cancer Discov,2016,6(10):1134-1147.
[5]程宇凌,敖竹君,陈伟,等.移植型和基因工程型乳腺癌动物模型研究进展[J].遵义医学院学报,2016,39(3):319-325.
[6]Ma F,Zhu W J,Guan Y F,et al.ctDNA dynamics:a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2therapy[J].Oncotarget,2016,7(40):66020-66031.
[7]Mutlu M,Saatci9,Ansari S A,et al.miR-564acts as a dual inhibitor of PI3Kand MAPK signaling networks and inhibits proliferation and invasion in breast cancer[J].Sci Rep,2016,6:32541.
[8]陈延松,金功圣,兰亚东,等.凋亡抑制蛋白抑制剂LCL161对人乳腺癌MDA-MB-231细胞增殖的影响[J].中华乳腺病杂志(电子版),2016,10(3):142-145.
[9]Wei A W,Fan B,Zhao Y J,et al.ST6Gal-I overexpression facilitates prostate cancer progression via the PI3K/Akt/GSK-3β/β-catenin signaling pathway[J].Oncotarget,2016,7(40):65374-65388.
[10]周武,曹明国,许军,等.鸟苷三磷酸酶活化蛋白Git2对乳腺癌转移的影响[J].中华肿瘤杂志,2016,38(7):492-498.
[11]Vuylsteke P,Huizing M,Petrakova K,et al.Pictilisib PI3Kinase inhibitor(aphosphatidylinositol 3-kinase[PI3K]inhibitor)plus paclitaxel for the treatment of hormone receptor-positive,HER2-negative,locally recurrent,or metastatic breast cancer:Interim analysis of the multicentre,placebo-controlled,phase II randomised PEGGY study[J].Ann Oncol,2016,27(11):2059-2066.
[12]余和平,崔乐,王必蓉,等.青蒿素抑制小鼠移植乳腺癌MT40及下调CD71表达[J].中华实验外科杂志,2016,33(6):1652.
[13]Qian J C,Chen Y Q,Meng T,et al.Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer[J].Oncotarget,2016,7(41):67071-67086.
[14]李荣晖,马武,张淑莲,等.哺乳动物雷帕霉素靶蛋白抑制剂在乳腺癌治疗中的研究进展[J].肿瘤研究与临床,2015,27(9):646-648.
[15]She Q B,Gruvberger-Saal S K,Maurer M,et al.Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer[J].BMC Cancer,2016,16:587.
[16]潘承欣,崔仁忠,吴绮鋆,等.曲妥珠单抗联合NSC 74859对曲妥珠耐药的乳腺癌细胞的抑制作用研究[J].现代生物医学进展,2016,16(7):1253-1256.
[17]Yadav R R,Guru S K,Joshi P,et al.6-Aryl substituted 4-(4-cyanomethyl)phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors[J].Eur J Med Chem,2016,122:731-743.
[18]陈军,赵文晖,刘玲玲,等.异丙酚通过激活PI3K/Akt信号通路抑制癌细胞转移[J].西安交通大学学报(医学版),2016,37(2):226-229.
[19]袁翠堂,丁罡,廖志军,等.大鼠乳腺癌骨转移模型中PI3K/Akt信号通路参与诱导疼痛[J].实用癌症杂志,2016,31(3):349-352,358.