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蛋白质精氨酸甲基转移酶1(PRMT1)是近年来新发现的一种表观遗传修饰酶,在膀胱癌等多种癌组织中过度表达,因此针对该靶点的新型表观抗肿瘤药物研究尤为重要.通过基于PRMT1药效团虚拟筛选模型筛查抑制PRMT1活性的小分子化合物,体外研究了靶向PRMT1的小分子化合物DB75对膀胱癌细胞的抗瘤活性及诱导细胞凋亡的分子机制.实验结果显示:通过筛选体系获得了能显著抑制PRMT1活性的小分子化合物DB75;MTT实验表明,DB75能够显著(P<0.05)地抑制膀胱癌T24细胞的增殖,且随着药物浓度的增加,抑制率呈明显的剂量效应,48 h半数抑制浓度IC50为2.2μmol/L;DAPI染色显示DB75能显著(P<0.05)诱导膀胱癌T24细胞凋亡;分子机制研究显示,DB75通过激活Caspase-3和PARP活性从而诱导T24细胞凋亡.以上结果初步表明DB75可作为一种新型的膀胱癌表观先导化合物.
Protein arginine methyltransferase 1 (PRMT1) is a newly discovered epigenetic modification enzyme in recent years. It is overexpressed in many cancerous tissues such as bladder cancer. Therefore, a new type of apparent antitumor drug Is particularly important.By screening small molecular compounds that inhibit the activity of PRMT1 based on the virtual screening model of PRMT1 pharmacophore, the anti-tumor activity and the molecular mechanism of inducing apoptosis of bladder cancer cell line DB75, a small molecule compound targeting PRMT1, were studied in vitro The results showed that DB75 could inhibit the proliferation of bladder cancer T24 cells significantly (P <0.05) by the screening system, and the small molecule compound DB75 that could significantly inhibit the activity of PRMT1 was obtained by MTT assay. With the increase of drug concentration, The inhibitory rate was obviously dose-effect, IC50 was 2.2μmol / L at 48 h; DAPI staining showed that DB75 could significantly (P <0.05) induce the apoptosis of bladder cancer T24 cells; the molecular mechanism indicated that DB75 could activate Caspase-3 And PARP activity to induce apoptosis of T24 cells.The above results initially indicated that DB75 could be used as a novel epigenetic lead compound of bladder cancer.