质子型双菲啰啉的特异性抗肿瘤活性及其机制研究

Specific antitumor activity and mechanism of protonic bis-phenanthroline

肝细胞癌(hepatocellular carcinoma,HCC)是常见的恶性肿瘤,其发病率高且极易转移复发,严重影响人类健康。传统药物治疗存在不良反应大、多药耐药等问题,因此亟须寻找新的药物和作用靶点。本研究合成了质子型的双菲啰啉(protonic bis-phenanthroline,H-BP),结果显示H-BP可选择性地抑制肿瘤细胞增殖,引起肝癌细胞凋亡;在HCC荷瘤小鼠体内,H-BP能够有效阻止瘤块的生长,在中剂量(5 mg·kg^(-1))和高剂量(10 mg·kg^(-1))时甚至可完全消除肿瘤,并对小鼠体重没有明显影响。实验方案由西南大学动物实验伦理委员会批准,严格按照动物使用和护理的伦理原则进行实验操作。机制研究表明,H-BP引起HCC凋亡的原因与H-BP降低了原癌基因转录因子多形性腺瘤基因样蛋白2(pleomorphic adenoma gene like-2,PLAGL2)的表达有关,造成PLAGL2下游蛋白缺氧诱导因子和β连环蛋白的下调,从而引发癌细胞死亡。本研究不仅使用氢键二聚化方法合成化合物,为药物的设计提供新的思路,而且实验结果表明PLAGL2可能是肿瘤治疗中的一个有效靶标。

Hepatocellular carcinoma(HCC)is a common malignant tumor worldwise.The incidence rate of HCC is high and is easy to metastasis and recurrence,which seriously affects human health.Traditional chemical drugs have some challenges such as toxicity,side effects,and multidrug resistance,thus it is urgent to find new drugs and effective targets.Here we synthesized a novel chemical,protonic bis-phenanthroline(H-BP),and the antitumor effect was investigated in the study.The results showed that H-BP could selectively inhibit the proliferation of tumor cells and cause HCC apoptosis.And also,in HCC tumor-bearing mice,H-BP could effectively prevent the growth of tumor mass,even completely eliminate the tumor at medium dose(5 mg·kg^(-1))and high dose(10 mg·kg^(-1)),and meanwhile H-BP has no significant effect on the body weight of mice.The experimental protocol was approved by the Animal Ethics Committee of Southwest University,and the experimental operation was strictly carried out in accordance with the ethical principles of animal use and care.Mechanism studies showed that H-BP induced HCC apoptosis was related to down-regulation the expression of pleomorphic adenoma gene like-2(PLAGL2),a oncogene transcription factor,resulting in the down-regulation of PLAGL2 downstream proteins hypoxia inducible factor andβ-catenin.This study not only introduces the dimerization method to form novel compounds that will provide a new approach for drug design,but also suggests that PLAGL2 may be an effective target in tumor therapy.