Division of Applied Radiation Bioscience, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea.
Radiation Non-Clinic Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea.
Int J Oncol. 2018 Aug;53(2):703-712. doi: 10.3892/ijo.2018.4424. Epub 2018 May 31.
Cyclin-dependent kinases (CDK) are considered to be potential targets of anticancer drugs that can interrupt the uncontrolled division of cancer cells. In this study, we selected two selective CDK inhibitors, AT7519 and SNS‑032, from current clinical trials and examined their anticancer and radiosensitizing effects in a cervical cancer model. SNS‑032 was found to be more potent than AT7519, with a lower half maximal inhibitory concentration (IC50) value. Both AT7519 and SNS‑032 induced the apoptosis, premature senescence and cytostasis of cervical cancer cells, which led to the attenuation of tumor growth in vivo. Moreover, using these CDK inhibitors together with radiation synergistically inhibited tumor growth in a human xenograft tumor model. The concomitant activation of the p53 tumor suppressor and the suppression of cell cycle checkpoint responses mediated by Chk1 led to the cytostasis of cervical cancer cells. Finally, AT7519 and SNS‑032 inhibited cancer cell migration, invasion and angiogenesis in vitro, and suppressed lung metastases in a spontaneous metastasis model. On the whole, the findings of this study indicate that the utilization of AT7519 and SNS‑032 as part of an adjuvant treatment may help control cervical cancer progression.
细胞周期蛋白依赖性激酶（CDK）被认为是抗癌药物的潜在靶点，可以阻断癌细胞的失控分裂。在本研究中，我们从当前的临床试验中选择了两种选择性 CDK 抑制剂 AT7519 和 SNS-032，并在宫颈癌模型中研究了它们的抗癌和放射增敏作用。结果发现，SNS-032 比 AT7519 更有效，其半最大抑制浓度（IC50）值更低。AT7519 和 SNS-032 均可诱导宫颈癌细胞凋亡、衰老和细胞周期停滞，从而抑制体内肿瘤生长。此外，这些 CDK 抑制剂与放疗联合使用可协同抑制人异种移植肿瘤模型中的肿瘤生长。p53 肿瘤抑制因子的同时激活和 Chk1 介导的细胞周期检查点反应的抑制导致宫颈癌细胞的细胞周期停滞。最后，AT7519 和 SNS-032 抑制了宫颈癌细胞的迁移、侵袭和血管生成，并抑制了自发转移模型中的肺转移。总的来说，本研究的结果表明，将 AT7519 和 SNS-032 用作辅助治疗的一部分可能有助于控制宫颈癌的进展。
