新型靶向组蛋白去乙酰化酶抑制剂的抗肿瘤作用及其机制

Antitumor effects and molecular mechanisms of novel selective HDAC inhibitors in human cervix carcinoma HeLa cells

探讨3种新型靶向组蛋白去乙酰化酶(HDAC)抑制剂D16,D22,D29的抗肿瘤活性作用及其抑制人宫颈癌细胞增殖的机制。MTT法检测D16,D22,D29对MCF-7、HCT-116、A549、HeLa以及K562的增殖抑制作用;测定D16,D22,D29对HDAC及其HDAC-1的酶活抑制作用;流式细胞术观察D16,D22,D29对HeLa细胞周期及凋亡诱导作用;Western blot测定D16,D22,D29对HeLa细胞中乙酰化组蛋白H3(Ac-H3),p21cip/WAF的蛋白表达影响。结果显示,D16,D22,D29明显抑制多种肿瘤细胞株的增殖,有效抑制HDAC及其HDAC-1的活性,其效果优于阳性对照药Vorinostat(SAHA),并诱导HeLa细胞产生G1期细胞周期阻滞及凋亡,Ac-H3及p21cip/WAF的蛋白水平明显上升。D16,D22,D29具有一定的抗肿瘤活性,其机制与诱导细胞周期阻滞和凋亡产生,促进p21cip/WAF的蛋白表达有关。

Examine the antitumor activity of three new histone deacetylase（HDAC） and HDAC-1 inhibitors with the carboline structure named D16,D22,D29 and explore the molecular mechanisms underlying.The anti-proliferative effects were detected by MTT assays in MCF-7,HCT-116,A549,HeLa and K562.The inhibition in HDAC and HDAC-1 were detected by using fluorescent substrate.The effects on the cell cycle arrest and apoptosis induction were examined by flow cytometry.The protein expressions of acetylated-H3 and p21cip/WAF were detected by Western blotting.D16,D22,and D29 inhibited the proliferation of multiple carcinoma cells at much lower concentrations than SAHA dose-dependently.D16,D22,D29 effectively inhibited the activity of HDAC and HDAC-1;D16,D22 and D29 induced G1 phase cell cycle arrest and apoptosis while the protein expression of acetylation of histone H3 and p21cip/WAF were significantly up-regulated.D16,D22 and D29 were potent antitumor agents with their cycle arrest and apoptosis mechanisms.The molecualar mechanisms were associated with the promotion of acetylated-H3 and p21cip/WAF.