Pterostilbene inhibits hepatocellular carcinoma proliferation and HBV replication by targeting ribonucleotide reductase M2 protein.
Pterostilbene inhibits hepatocellular carcinoma proliferation and HBV replication by targeting ribonucleotide reductase M2 protein.
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发表时间：
2021
影响因子：
5.3
通讯作者：
Rui Wang;Zhijian Xu;Jia-li Tian;Qian Liu;Jingwen Dong;Lijuan Guo;Boning Hai;Xia Liu;H. Yao;Zhi Chen;Junjie Xu;Lijun Zhu;Haiyi Chen;Tingjun Hou;Weiliang Zhu;Jimin Shao
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作者：
Rui Wang;Zhijian Xu;Jia-li Tian;Qian Liu;Jingwen Dong;Lijuan Guo;Boning Hai;Xia Liu;H. Yao;Zhi Chen;Junjie Xu;Lijun Zhu;Haiyi Chen;Tingjun Hou;Weiliang Zhu;Jimin Shao
肝细胞癌是世界上最致命的疾病之一。HBV感染是HCC的致病因素，与HCC的发展密切相关。核糖核苷酸还原酶（RR）是细胞DNA合成的关键酶，在生存率较低的HCC中，RR小亚基M2 （RRM2）高度上调。我们之前已经证明HBV可以激活RRM2的表达和RR酶的活性，从而在宿主肝细胞中进行病毒DNA复制。因此，RRM2可能是HCC和hbv相关HCC的重要治疗靶点。紫菀芪是一种天然植物成分，通过与RRM2蛋白的相互作用，有效抑制体外RR酶活性，IC50约为0.62 μM，远高于现有的RRM2抑制药物。紫檀芪对肝癌细胞增殖的抑制作用，其MTT IC50约为20 ~ 40 μM，抑制肝癌细胞DNA合成，阻滞细胞周期于S期，导致细胞凋亡。另一方面，该化合物在HBV基因组整合和新转染的HCC细胞中显著抑制HBV DNA复制，抑制HBV复制的EC50显著低于抑制HCC增殖的IC50。值得注意的是，紫檀芪对索拉非尼和拉米夫定耐药的HCC细胞具有相似的抑制活性。此外，加入dNTP前体后，紫花蓟花碱对HCC增殖和HBV复制的抑制作用被显著逆转，表明RR是该化合物的细胞内靶点。最后，在裸鼠实验中，紫檀碱能有效抑制肝癌异种移植物生长，且毒性较低。本研究表明，紫檀芪是一种新的有效的靶向RRM2的RR抑制剂。它可以同时抑制HCC增殖和HBV复制，具有治疗HCC和HBV相关HCC的潜在新用途。
Hepatocellular carcinoma (HCC), one of the most deadly diseases all around the world. HBV infection is a causative factor of HCC and closely associated with HCC development. Ribonucleotide reductase (RR) is a key enzyme for cellular DNA synthesis and RR small subunit M2 (RRM2) is highly upregulated in HCC with poor survival rates. We have previously shown that HBV can activate the expression of RRM2 and the activity of RR enzyme for the viral DNA replication in host liver cells. Thus, RRM2 may be an important therapeutic target for HCC and HBV-related HCC. Pterostilbene, a natural plant component, potently inhibited in vitro RR enzyme activity with the IC50 of about 0.62 μM through interacting with RRM2 protein, which was much higher than current RRM2 inhibitory drugs. Pterostilbine inhibited cell proliferation with an MTT IC50 of about 20-40 μM in various HCC cell lines, causing DNA synthesis inhibition, cell cycle arrest at S phase, and accordingly apoptosis. On the other hand, the compound significantly inhibited HBV DNA replication in HBV genome integrated and newly transfected HCC cells, and the EC50 for inhibiting HBV replication was significantly lower than the IC50 for inhibiting HCC proliferation. Notably, pterostilbene possessed a similar inhibitory activity in sorafenib and lamivudine resistant HCC cells. Moreover, the inhibitory effects of pterostilbine against HCC proliferation and HBV replication were significantly reversed by addition of dNTP precursors, suggesting that RR was the intracellular target of the compound. Finally, pterostilbine effectively inhibited HCC xenograft growth with a relatively low toxicity in nude mouse experiments. This study demonstrates that pterostilbene is a novel potent RR inhibitor by targeting RRM2. It can simultaneously inhibit HCC proliferation and HBV replication with a potential new use for treatment of HCC and HBV-related HCC.