4-Acetylantroquinonol B induced DNA damage response signaling and apoptosis via suppressing CDK2/CDK4 expression in triple negative breast cancer cells

Pamungkas Bagus Satriyo, Chih Ming Su, Jiann Ruey Ong, Wen Chien Huang, Iat Hang Fong, Chih Cheng Lin, Teguh Aryandono, Sofia Mubarika Haryana, Li Deng, Chun Chih Huang, Yew Min Tzeng, Tsu Yi Chao, Hui Wen Liu, Chi Tai Yeh

研究成果: 雜誌貢獻文章同行評審

摘要

Background: 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. Methods: 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. Results: 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. Conclusion: 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.
原文英語
文章編號115493
期刊Toxicology and Applied Pharmacology
422
DOIs
出版狀態已發佈 - 七月 1 2021

ASJC Scopus subject areas

  • 毒理學
  • 藥理

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