Inhibition of CDC25B With WG-391D Impedes the Tumorigenesis of Ovarian Cancer
Inhibition of CDC25B With WG-391D Impedes the Tumorigenesis of Ovarian Cancer
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用 WG-391D 抑制 CDC25B 可阻止卵巢癌的肿瘤发生
DOI：
10.3389/fonc.2019.00236
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发表时间：
2019-04-08
影响因子：
4.7
通讯作者：
Zhang, Rong
中科院分区：
文献类型：
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作者：
Xiao, Yangjiong;Yu, Yang;Zhang, Rong
因此，迫切需要新的抑制剂作为靶向治疗，以提高卵巢癌患者的总生存期（OS）。在这里，我们发现细胞分裂周期25 B（CDC 25 B）在卵巢肿瘤中过度表达，并与患者预后不良相关。所有先前报道的CDC 25 B抑制剂都是通过它们在体外可逆地抑制CDC 25 B的催化去磷酸化活性的能力来鉴定的;然而，这些化合物都没有进入卵巢癌治疗的临床试验。在这项研究中，我们合成了一种新的小分子化合物WG-391 D，它可以有效地下调CDC 25 B的表达，而不影响其催化去磷酸化活性。WG-391 D对CDC 25 B的抑制作用是不可逆的，因此WG-391 D应该对卵巢癌表现出有效的抗肿瘤活性。WG-391 D诱导细胞周期进展停滞在G2/M期。WG-391 D抑制8种代表性卵巢癌细胞系增殖和迁移的半数最大抑制浓度（IC 50）值（SKOV 3、ES 2、OVCAR 8、OVTOKO、A2780、IGROV 1、HO 8910 PM和MCAS）和五种原发性卵巢肿瘤细胞系（GFY 004、GFY 005、CZ 001、CZ 006和CZ 008）分别低于10和1 μM。WG-391 D抑制接种SKOV 3细胞或患者来源的异种移植物（PDX）的裸鼠中的肿瘤生长。其潜在机制与CDC 25 B的下调以及随后的细胞分裂周期2（CDC 2）和丝氨酸/苏氨酸激酶（AKT）的失活有关。总之，本研究表明WG-391 D对卵巢癌具有较强的抗肿瘤活性，并表明抑制剂下调CDC 25 B可为卵巢癌治疗提供理论依据。
Novel inhibitors are urgently needed for use as targeted therapies to improve the overall survival (OS) of patients with ovarian cancer. Here, we show that cell division cycle 25B (CDC25B) is over-expressed in ovarian tumors and associated with poor patient prognosis. All previously reported CDC25B inhibitors have been identified by their ability to reversibly inhibit the catalytic dephosphorylation activity of CDC25B in vitro; however, none of these compounds have entered clinical trials for ovarian cancer therapy. In this study, we synthesized a novel small molecule compound, WG-391D, that potently down-regulates CDC25B expression without affecting its catalytic dephosphorylation activity. The inhibition of CDC25B by WG-391D is irreversible, and WG-391D should therefore exhibit potent antitumor activity against ovarian cancer. WG-391D induces cell cycle progression arrest at the G2/M phase. Half maximal inhibitory concentration (IC50) values of WG-391D for inhibition of the proliferation and migration of eight representative ovarian cancer cell lines (SKOV3, ES2, OVCAR8, OVTOKO, A2780, IGROV1, HO8910PM, and MCAS) and five primary ovarian tumor cell lines (GFY004, GFY005, CZ001, CZ006, and CZ008) were lower than 10 and 1 μM, respectively. WG-391D inhibited tumor growth in nude mice inoculated with SKOV3 cells or a patient-derived xenograft (PDX). The underlying mechanisms were associated with the down-regulation of CDC25B and subsequent inactivation of cell division cycle 2 (CDC2) and the serine/threonine kinase, AKT. In conclusion, this study demonstrates that WG-391D exhibits strong antitumor activity against ovarian cancer and indicates that the down-regulation of CDC25B by inhibitors could provide a rationale for ovarian cancer therapy.