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

Abstract

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.

• Authors: 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
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 422 Pg. 115493 (07 01 2021) ISSN: 1096-0333 [Electronic] United States
• PMID: 33727089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• Cyclohexanones
• 4-acetylantroquinonol B
• CDK2 protein, human
• CDK4 protein, human
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 2 (genetics, metabolism)
• Cyclin-Dependent Kinase 4 (genetics, metabolism)
• Cyclohexanones (pharmacology)
• DNA Damage
• DNA Repair (drug effects)
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice, Inbred NOD
• Mice, SCID
• Signal Transduction
• Triple Negative Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• Mice