A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel.
A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel.
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DOI：
10.1158/1078-0432.ccr-16-1562
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发表时间：
2017-04-15
期刊：
影响因子：
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通讯作者：
Bast RC Jr
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文献类型：
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作者：
Zhou J;Alfraidi A;Zhang S;Santiago-O'Farrill JM;Yerramreddy Reddy VK;Alsaadi A;Ahmed AA;Yang H;Liu J;Mao W;Wang Y;Takemori H;Vankayalapati H;Lu Z;Bast RC Jr
SIK 2是有丝分裂纺锤体形成所需的中心体激酶，是卵巢癌治疗的潜在靶点。在这里，我们研究了一种新的小分子SIK 2抑制剂ARN-3236对卵巢癌对紫杉醇敏感性的影响。在卵巢癌组织样品和细胞系中测定SIK 2表达。在卵巢癌细胞系的培养物和异种移植物中测试ARN-3236抑制生长和增强紫杉醇敏感性的效率。比较SIK 2 siRNA和ARN-3236产生核-中心体解离、抑制中心体分裂、阻断有丝分裂进程、诱导四倍体、触发凋亡性细胞死亡和减少AKT/存活素信号传导的能力。SIK 2在大约30%的高级别浆液性卵巢癌中过表达。ARN-3236抑制10种卵巢癌细胞系的生长，IC 50为0.8 - 2.6 μM，其中ARN-3236的IC 50与内源性SIK 2表达呈负相关（Pearson r =-0.642，P = 0.03）。ARN-3236增强了10种细胞系中的8种以及SKOv 3 ip（P = 0.028）和OVCAR 8异种移植物对紫杉醇的敏感性。在至少三种细胞系中观察到协同相互作用。ARN-3236在分裂间期使中心体与细胞核解偶联，阻断中心体在有丝分裂中的分离，引起前中期阻滞并诱导凋亡性细胞死亡和四倍体。ARN-3236还抑制AKT磷酸化并减弱存活素表达。ARN-3236是第一个在临床前模型中评估针对卵巢癌的口服SIK 2抑制剂，并显示出抑制卵巢癌生长和增强紫杉醇化疗敏感性的前景。
SIK2 is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy. Here we examine the effects of a novel small molecule SIK2 inhibitor, ARN-3236, on sensitivity to paclitaxel in ovarian cancer. SIK2 expression was determined in ovarian cancer tissue samples and cell lines. ARN-3236 was tested for its efficiency to inhibit growth and enhance paclitaxel sensitivity in cultures and xenografts of ovarian cancer cell lines. SIK2 siRNA and ARN-3236 were compared for their ability to produce nuclear-centrosome dissociation, inhibit centrosome splitting, block mitotic progression, induce tetraploidy, trigger apoptotic cell death and reduce AKT/survivin signaling. SIK2 is overexpressed in approximately 30% of high grade serous ovarian cancers. ARN-3236 inhibited growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 μM, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearson’s r = −0.642, P = 0.03). ARN-3236 enhanced sensitivity to paclitaxel in 8 of 10 cell lines, as well as in SKOv3ip (P = 0.028) and OVCAR8 xenografts. In at least three cell lines a synergistic interaction was observed. ARN-3236 uncoupled the centrosome from the nucleus in interphase, blocked centrosome separation in mitosis, caused prometaphase arrest and induced apoptotic cell death and tetraploidy. ARN-3236 also inhibited AKT phosphorylation and attenuated survivin expression. ARN-3236 is the first orally available inhibitor of SIK2 to be evaluated against ovarian cancer in preclinical models and shows promise in inhibiting ovarian cancer growth and enhancing paclitaxel chemosensitivity.