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4-Acetylantroquinonol B induced DNA damage response signaling and apoptosis via suppressing CDK2/CDK4 expression in triple negative breast cancer cells
- Source :
- Toxicology and applied pharmacology. 422
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
Cell cycle checkpoint
DNA Repair
DNA damage
Down-Regulation
Apoptosis
Triple Negative Breast Neoplasms
Mice, SCID
Toxicology
03 medical and health sciences
0302 clinical medicine
Breast cancer
4-Butyrolactone
Cyclin-dependent kinase
Mice, Inbred NOD
Cell Line, Tumor
medicine
Animals
Humans
Triple-negative breast cancer
Cell Proliferation
Pharmacology
biology
Kinase
Chemistry
Cyclohexanones
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cell Cycle Checkpoints
medicine.disease
Antineoplastic Agents, Phytogenic
Xenograft Model Antitumor Assays
Tumor Burden
Gene Expression Regulation, Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
Cancer research
Female
Cyclin-dependent kinase 6
biological phenomena, cell phenomena, and immunity
DNA Damage
Signal Transduction
Subjects
Details
- ISSN :
- 10960333
- Volume :
- 422
- Database :
- OpenAIRE
- Journal :
- Toxicology and applied pharmacology
- Accession number :
- edsair.doi.dedup.....724fbb58bd33a8d7d0443af65844c418