Satriyo Pamungkas Bagus, Su Chih Ming, Ong Jiann Ruey, Huang Wen-Chien, Fong Iat-Hang, Lin Chih-Cheng, Aryandono Teguh, Haryana Sofia Mubarika, Deng Li, Huang Chun-Chih, Tzeng Yew-Min, Chao Tsu-Yi, Liu Hui-Wen, Yeh Chi-Tai
College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan; Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia; Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia.
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Toxicol Appl Pharmacol. 2021 Jul 1;422:115493. doi: 10.1016/j.taap.2021.115493. Epub 2021 Mar 13.
Triple-negative breast cancer (TNBC) has a more aggressive phenotype and poorer prognosis than hormone receptor (HR+) and human epidermal growth factor receptor (HER2 -) subtypes. Inhibition of cyclin-dependent kinase (CDK)4 and CDK6 was successful in patients with advanced metastatic HR+/HER2- breast cancer, but those with TNBC exhibited low or no response to this therapeutic approach. This study investigated the dual therapeutic targeting of CDK2 and CDK4 by using 4-acetyl-antroquinonol B (4-AAQB) against TNBC cells.
We examined the effects of CDK2, CDK4, and CDK6 inhibition through 4-AAQB treatment on TNBC cell lines and established an orthotropic xenograft mouse model to confirm the in vitro results of inhibiting CDK2, CDK4, and CDK6 by 4-AAQB treatment.
High expression and alteration of CDK2 and CDK4 but not CDK6 significantly correlated with poor overall survival of patients with breast cancer. CDK2 and CDK4 were positively correlated with damage in DNA replication and repair pathways. Docking results indicated that 4-AAQB was bound to CDK2 and CDK4 with high affinity. Treatment of TNBC cells with 4-AAQB suppressed the expression of CDK2 and CDK4 in vitro. Additionally, 4-AAQB induced cell cycle arrest, DNA damage, and apoptosis in TNBC cells. In vivo study results confirmed that the anticancer activity of 4-AAQB suppressed tumor growth through the inhibition of CDK2 and CDK4.
The expression level of CDK2 and CDK4 and DNA damage response (DDR) signaling are prominent in TNBC cell cycle regulation. Thus, 4-AAQB is a potential agent for targeting CDK2/4 and DDR in TNBC cells.
三阴性乳腺癌（TNBC）具有比激素受体（HR+）和人表皮生长因子受体2（HER2-）亚型更具侵袭性的表型和更差的预后。细胞周期蛋白依赖性激酶（CDK）4和CDK6的抑制在晚期转移性HR+/HER2-乳腺癌患者中取得成功，但TNBC患者对这种治疗方法表现出低反应或无反应。本研究通过使用4-乙酰安罗替尼醇B（4-AAQB）针对TNBC细胞研究CDK2和CDK4的双重治疗靶向作用。
我们通过4-AAQB处理检测了对TNBC细胞系中CDK2、CDK4和CDK6抑制的影响，并建立了原位异种移植小鼠模型以证实4-AAQB处理抑制CDK2、CDK4和CDK6的体外结果。
CDK2和CDK4而非CDK6的高表达和改变与乳腺癌患者较差的总生存期显著相关。CDK2和CDK4与DNA复制和修复途径中的损伤呈正相关。对接结果表明4-AAQB以高亲和力与CDK2和CDK4结合。用4-AAQB处理TNBC细胞在体外抑制了CDK2和CDK4的表达。此外，4-AAQB诱导TNBC细胞的细胞周期停滞、DNA损伤和凋亡。体内研究结果证实4-AAQB的抗癌活性通过抑制CDK2和CDK4抑制肿瘤生长。
CDK2和CDK4的表达水平以及DNA损伤反应（DDR）信号在TNBC细胞周期调控中很突出。因此，4-AAQB是靶向TNBC细胞中CDK2/4和DDR的潜在药物。
