In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83
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Cancer is regarded as a proliferative disorder. Inhibition of cyclin-dependent kinases (CDKs), which are the key regulators of the cell-cycle and RNA transcription, represents an attractive strategy for cancer therapy. In this study, we report the cellular mechanistic investigation of CDKI-83, a K i-nanomolar CDK9 inhibitor. The compound shows effective anti-proliferative activity in human tumour cell lines with GI50 <1 μM, and is capable of inducing apoptosis in A2780 human ovarian cancer cells as determined by the activated caspase-3, Annexin V/PI double staining and accumulated cells at the sub-G1 phase of cell-cycle. While A2780 cells were arrested in G2/M phase with CDKI-83 treatment, phosphorylation at Thr320 of PP1α was significantly reduced, indicating CDK1 inhibition. Importantly, this compound reduced phosphorylation at Ser-2 of RNA polymerase II (RNAPII) by inhibiting cellular CDK9 activity, and down-regulated Mcl-1 and Bcl-2. These results suggest that combined inhibition of CDK9 and CDK1 may result in the effective induction of apoptosis and CDKI-83 has the potential to be developed as an anti-cancer agent.
KeywordsCyclin-dependent kinase Anti-cancer agent RNAPII transcription PTEF-b CDK9 inhibitor Mcl-1 Bcl-2
This study was supported in part by the Cancer Research UK grant C21568/A8988. The authors would like to thank Dr Scott Roberts for his technical assistant with RT-PCR.
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