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A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction
- Source :
- Investigational New Drugs. 38:700-713
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G0/G1 phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 μM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.
- Subjects :
- 0301 basic medicine
BRD4
Programmed cell death
Cell cycle checkpoint
Mice, Nude
Apoptosis
Resting Phase, Cell Cycle
Epigenesis, Genetic
BET inhibitor
Mice
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Animals
Humans
Pharmacology (medical)
Cell Proliferation
Pharmacology
Mice, Inbred BALB C
Cell Death
Cell growth
Chemistry
G1 Phase
Proteins
Cell Cycle Checkpoints
Cell cycle
Xenograft Model Antitumor Assays
Bromodomain
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
A549 Cells
030220 oncology & carcinogenesis
PC-3 Cells
Cancer research
HT29 Cells
Subjects
Details
- ISSN :
- 15730646 and 01676997
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Investigational New Drugs
- Accession number :
- edsair.doi.dedup.....3138f32200f3dfd224627e4942e06b9a