Abstract
BackgroundAZD7762 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.MethodsWe 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.ResultsIn 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.ConclusionThese 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.
Highlights
1-(2-((S)-piperidin-3-ylcarbamoyl)-5-(3-fluorophenyl) thiophen-3-yl) urea (AZD7762) is a checkpoint kinase 1 (Chk 1) inhibitor, which has been reported to sensitize many tumor cells to DNA damage
The inhibitory effect of AZD7762 on the proliferation of human osteosarcoma cell lines The inhibitory effect of Chk1 inhibitor AZD7762 was studied on the proliferation of two human osteosarcoma cell lines
In summary, our study confirmed that AZD7762 can reduce DNA damage induced by cisplatin through inhibiting the activation of G2/M cell cycle checkpoints and regulating Chk1-Cdc25C-Cdc2/Cyclin-B1 cell signaling pathways
Summary
AZD7762 is a checkpoint kinase 1 (Chk 1) inhibitor, which has been reported to sensitize many tumor cells to DNA damage. Whether AZD7762 could sensitize osteosarcoma cells to chemotherapy cisplatin has not been defined. Cisplatin could bind to purine and pyrimidine bases of DNA to form crosslinks between chains, which damages cellular DNA and causes cancer cells to die. The damage of DNA can activate multiple cell cycle checkpoints (G1/S, S, G2/M) and arrest the cell cycle at the detection point for DNA repair. This is a cell’s self-protection mechanism, and inhibition of this mechanism can enhance the role of the chemotherapeutic drug
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