Zhu Jian, Zou Hanhui, Yu Wei, Huang Yuluan, Liu Bing, Li Tao, Liang Chengzhen, Tao Huimin
1Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jie Fang Road, Hangzhou, 310009 Zhejiang People's Republic of China.
2Orthopedics Research Institute of Zhejiang University, #88, Jiefang Road, Hangzhou, 310009 China.
Cancer Cell Int. 2019 Jul 27;19:195. doi: 10.1186/s12935-019-0896-9. eCollection 2019.
AZD7762 is a checkpoint kinase 1 (Chk 1) inhibitor, which has been reported to sensitize many tumor cells to DNA damage. However, whether AZD7762 could sensitize osteosarcoma cells to chemotherapy cisplatin has not been defined.
We used a variety of methods such as cell viability assays, flow cytometry, western blotting, and immunohistochemistry analysis to determine AZD7762 enhancing cisplatin-induced apoptosis on osteosarcoma cell lines in vitro and in vivo.
In the present study, we demonstrated that AZD7762 could enhance cisplatin-mediated apoptosis and mitotic catastrophe of osteosarcoma cells in vitro, and promote the inhibition of xenograft growth induced by cisplatin in vivo. The mechanistic study indicated that AZD7762 enhance the effect of cisplatin through abrogating cisplatin-mediated G2/M arrest and inhibiting the cisplatin damage repair as demonstrated by increasing cisplatin-induced γH2AX expression.
These results suggest that AZD7762 could effectively promote cisplatin-induced apoptosis and mitotic catastrophe in osteosarcoma cells. The clinical application of AZD7762 as an adjuvant in the chemotherapy of osteosarcoma should be further explored.
AZD7762是一种关卡激酶1（Chk 1）抑制剂，据报道它能使许多肿瘤细胞对DNA损伤敏感。然而，AZD7762是否能使骨肉瘤细胞对化疗药物顺铂敏感尚未明确。
我们使用了多种方法，如细胞活力测定、流式细胞术、蛋白质印迹法和免疫组织化学分析，以确定AZD7762在体外和体内增强顺铂诱导骨肉瘤细胞系凋亡的情况。
在本研究中，我们证明AZD7762在体外可增强顺铂介导的骨肉瘤细胞凋亡和有丝分裂灾难，并在体内促进顺铂诱导的异种移植瘤生长抑制。机制研究表明，AZD7762通过消除顺铂介导的G2/M期阻滞并抑制顺铂损伤修复来增强顺铂的作用，这表现为顺铂诱导的γH2AX表达增加。
这些结果表明，AZD7762可有效促进顺铂诱导的骨肉瘤细胞凋亡和有丝分裂灾难。应进一步探索AZD7762作为骨肉瘤化疗辅助药物的临床应用。
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