School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
Invest New Drugs. 2012 Jun;30(3):889-97. doi: 10.1007/s10637-011-9641-5. Epub 2011 Feb 18.
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 GI(50) <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 G(2)/M phase with CDKI-83 treatment, phosphorylation at Thr(320) 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.
癌症被认为是一种增殖性疾病。抑制细胞周期和 RNA 转录的关键调节因子——周期蛋白依赖性激酶（CDKs），代表了癌症治疗的一种有吸引力的策略。在这项研究中，我们报告了 CDK1 抑制剂 CDKI-83 的细胞机制研究。该化合物在 GI（50）<1 μM 的人类肿瘤细胞系中表现出有效的抗增殖活性，并能够诱导 A2780 人卵巢癌细胞凋亡，这通过激活的 caspase-3、Annexin V/PI 双重染色和细胞周期的亚 G1 期累积细胞来确定。虽然 A2780 细胞在用 CDKI-83 处理时被阻滞在 G（2）/M 期，但 PP1α 的 Thr（320）磷酸化明显减少，表明 CDK1 抑制。重要的是，该化合物通过抑制细胞 CDK9 活性来降低 RNA 聚合酶 II（RNAPII）的 Ser-2 磷酸化，并下调 Mcl-1 和 Bcl-2。这些结果表明，联合抑制 CDK9 和 CDK1 可能导致有效的凋亡诱导，CDKI-83 有可能被开发为抗癌药物。
