RO-3306 抑制 CDK1 在卵巢癌细胞和卵巢癌转基因小鼠模型中表现出抗肿瘤作用,International Journal of Molecular Sciences

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RO-3306 抑制 CDK1 在卵巢癌细胞和卵巢癌转基因小鼠模型中表现出抗肿瘤作用
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2023-08-03 , DOI: 10.3390/ijms241512375
Yu Huang _{1,

2} , Yali Fan _{2,

3} , Ziyi Zhao _{2,

3} , Xin Zhang _{2,

3} , Katherine Tucker ₂ , Allison Staley ₂ , Hongyan Suo _{2,

3} , Wenchuan Sun ₂ , Xiaochang Shen _{2,

3} , Boer Deng _{2,

3} , Stuart R Pierce ₂ , Lindsay West ₂ , Yajie Yin ₂ , Michael J Emanuele _{4,

5} , Chunxiao Zhou _{2,

5} , Victoria Bae-Jump _{2,

5}

Affiliation

卵巢癌是美国最致命的生殖器官妇科恶性肿瘤。细胞周期蛋白依赖性激酶1（CDK1）是一种重要的细胞周期调节蛋白，特异性控制细胞周期的G2/M期转变。RO-3306 是一种选择性、ATP 竞争性、细胞渗透性 CDK1 抑制剂，在多种临床前模型中显示出有效的抗肿瘤活性。在本研究中，我们研究了CDK1表达对卵巢癌患者预后的影响以及RO-3306在卵巢癌细胞系和高级别浆液性卵巢癌基因工程小鼠模型（KpB）中的抗肿瘤作用。模型）。在 147 名上皮性卵巢癌患者中，与低表达组相比，CDK1 过表达与不良预后显着相关。RO-3306 显着抑制细胞增殖、诱导细胞凋亡、引起细胞应激并减少细胞迁移。用RO-3306治疗KpB小鼠4周，在肥胖和瘦条件下肿瘤重量显着下降，且没有明显副作用。总体而言，我们的结果表明，RO-3306抑制CDK1活性可有效减少细胞增殖和肿瘤生长，为未来CDK1抑制剂治疗卵巢癌的临床试验提供生物学证据。

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Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer.

更新日期：2023-08-05

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