Novel 2-phenyloxypyrimidine derivative induces apoptosis and autophagy via inhibiting PI3K pathway and activating MAPK/ERK signaling in hepatocellular carcinoma cells.
Novel 2-phenyloxypyrimidine derivative induces apoptosis and autophagy via inhibiting PI3K pathway and activating MAPK/ERK signaling in hepatocellular carcinoma cells.
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新型 2-苯氧基嘧啶衍生物通过抑制 PI3K 通路并激活 MAPK/ERK 信号传导诱导肝细胞癌细胞凋亡和自噬
DOI：
10.1038/s41598-018-29199-8
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发表时间：
2018-07-19
影响因子：
4.6
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Wang J;Sun P;Chen Y;Yao H;Wang S
肝细胞癌（HCC）是全球癌症相关死亡的第二大原因。由于大多数患者在疾病的晚期被诊断出来，多靶点酪氨酸激酶抑制剂索拉非尼是唯一有效性有限的药物。新的和有效的治疗方法是晚期HCC患者尚未满足的医疗需求。鉴于血小板源性生长因子受体α（PDGFRα）的异常表达和活性与肝癌的发病机制密切相关，本文通过对不同衍生物的比较，发现并鉴定了一种新的PDGFRα抑制剂N-（3-（（4-（苯并呋喃-2-基）嘧啶-2-基）氧基）-4-甲基苯基）-4-（（4-甲基哌嗪-1-基）甲基）苯甲酰胺（E5）。我们发现，E5抑制肝癌细胞的增殖和诱导凋亡。由于泛半胱天冬酶抑制剂Z-VAD-FMK部分地将HCC细胞从E5降低的细胞活力中拯救出来，因此随后研究了由E5引发的自噬细胞死亡。E5可诱导LC 3-I向LC 3-II转化，增加Atg 5的表达，恢复氯喹阻断的自噬流。同时，E5能够下调PDGFRα/PI 3 K/AKT/mTOR信号通路，激活MAPK/ERK信号通路。综上所述，除了E5作为有价值的候选药物的可能性外，本研究进一步支持靶向抑制PDGFRα是HCC有希望的治疗策略的观点。
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality globally. Because most patients are diagnosed at advanced stages of the disease, multi-targeted tyrosine kinase inhibitor sorafenib is the only available drug to show limited effectiveness. Novel and effective therapies are unmet medical need for advanced HCC patients. Given that the aberrant expression and activity of platelet-derived growth factor receptor α (PDGFRα) are closely associated with the pathogenesis of HCC, here we present the discovery and identification of a novel PDGFRα inhibitor, N-(3-((4-(benzofuran-2-yl)pyrimidin-2-yl)oxy)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (E5) after comparison of different derivatives. We found that E5 inhibited proliferation and induced apoptosis in HCC cells. Since the pan-caspase inhibitor Z-VAD-FMK partially rescued HCC cells from E5-reduced cell viability, autophagic cell death triggered by E5 was subsequently investigated. E5 could induce the conversion of LC3-I to LC3-II, increase the expression of Atg5 and restore the autophagy flux blocked by chloroquine. Meanwhile, E5 was able to downregulate the PDGFRα/PI3K/AKT/mTOR pathway and to activate MAPK/ERK signaling pathway. Taken together, in addition to the possibility of E5 as a valuable drug candidate, the present study further supports the notion that targeted inhibition of PDGFRα is a promising therapeutic strategy for HCC.
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DOI：
10.1158/1078-0432.ccr-12-0151
发表时间：
2012-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Villanueva A;Llovet JM
通讯作者：
Llovet JM
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
--
作者：
Yu JH;Kim JM;Kim JK;Choi SJ;Lee KS;Lee JW;Chang HY;Lee JI
通讯作者：
Lee JI
影响因子：
120.1
作者：
Dobbelstein, Matthias;Moll, Ute
通讯作者：
Moll, Ute
影响因子：
--
作者：
Perrin, Dominique;Fremaux, Christele;Scheer, Alexander
通讯作者：
Scheer, Alexander