Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth.
Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth.
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DOI：
10.1097/cad.0b013e32834ac8fc
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发表时间：
2011-11
影响因子：
2.3
通讯作者：
Burdette JE
中科院分区：
文献类型：
--
作者：
Hilliard TS;Gaisina IN;Muehlbauer AG;Gaisin AM;Gallier F;Burdette JE
卵巢癌是美国妇女中最致命的妇科恶性肿瘤。紫杉醇/卡铂是目前用于治疗卵巢癌的药物疗法，但大多数妇女会产生耐药性和疾病复发，需要替代治疗策略。癌症治疗的一个可能的分子靶点是糖原合成酶激酶3β（GSK 3 β），这是Wnt信号通路中的一种下游激酶，在浆液性卵巢癌中过表达。合成、筛选了基于马来酰亚胺的新型GSK 3 β抑制剂（GSK 3 βi），并使用SKOV 3和OVCA 432浆液性卵巢癌细胞系进行了体外测试。从一组10种抑制剂中，发现GSK 3 β 19 ING 41在体外最有效。4′6-二脒基-2-苯基吲哚（DAPI）阳性核凝聚、聚ADP核糖聚合酶（PARP）裂解和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色显示9 ING 41诱导细胞凋亡。凋亡的机制是通过caspase-3裂解。在OVCA 432和SKOV 3细胞系中，GSK 3 βi上调GSK 3 β抑制性丝氨酸残基的磷酸化，并抑制下游靶糖原合酶的磷酸化。使用SKOV 3细胞的体内异种移植物研究表明，肿瘤进展在体内被9 ING 41阻碍。大鼠中9 ING 41的最大耐受剂量大于500 mg/kg。药代动力学分析表明，9 ING 41的生物利用度为4.5%，在组织中分布良好。因此，单独使用GSK 3 β抑制剂或与现有药物联合使用可能会阻碍浆液性卵巢癌的生长。
Ovarian cancer is the most lethal gynecological malignancy among US women. Paclitaxel/carboplatin is the current drug therapy used to treat ovarian cancer, but most women develop drug resistance and recurrence of the disease, necessitating alternative strategies for treatment. A possible molecular target for cancer therapy is glycogen synthase kinase 3β (GSK3β), a downstream kinase in the Wnt signaling pathway that is overexpressed in serous ovarian cancer. Novel maleimide-based GSK3β inhibitors (GSK3βi) were synthesized, selected, and tested in vitro using SKOV3 and OVCA432 serous ovarian cancer cell lines. From a panel of 10 inhibitors, the GSK3βi 9ING41 was found to be the most effective in vitro. 9ING41 induced apoptosis as indicated by 4′6-diamidino-2-phenylindole (DAPI) positive nuclear condensation, poly (ADP-ribose) polymerase (PARP) cleavage, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The mechanism for apoptosis was through caspase-3 cleavage. GSK3βi upregulated phosphorylation of the inhibitory serine residue of GSK3β in the OVCA432 and SKOV3 cell lines as well as inhibited phosphorylation of the downstream target glycogen synthase. An in vivo xenograft study using SKOV3 cells demonstrated that tumor progression was hindered by 9ING41 in vivo. The maximum tolerated dose for 9ING41 was greater than 500 mg/kg in rats. Pharmacokinetic analysis showed 9ING41 to have a bioavailability of 4.5% and was well distributed in tissues. Therefore, GSK3β inhibitors alone or in combination with existing drugs may hinder growth of serous ovarian cancers.