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The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60
- Source :
- Cellular Physiology and Biochemistry, Vol 35, Iss 5, Pp 1943-1957 (2015)
- Publication Year :
- 2015
- Publisher :
- Cell Physiol Biochem Press GmbH & Co KG, 2015.
-
Abstract
- Background/Aims: The antileukemic potential of isoindigos make them desired candidates for understanding their mechanism of action. We have recently synthesized a novel group of pyridone-annelated isoindigos and identified the derivative 5'-Cl that is cytotoxic to various cancer cell lines. In the present study, we analyzed the effect of this compound on cell cycle of the promyelocytic leukemia cell line HL-60. Methods: HL-60 cells were treated with 5'-Cl and its effect on cell cycle stages were determined by flow cytometry. Expression of cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) were determined by Western blotting, and activation of CDKs was studied using kinase assays. Results: 5'-Cl remarkably arrested cell cycle in HL-60 cells at the G0/G1 phase in a dose and time-dependent manner. Furthermore, 5'-Cl treatment significantly inhibited expression of D-cyclins, CDK2 and CDK4 and suppressed phosphorylation of the retinoblastoma protein Rb, whereas it increased the level of CKI p21. Molecular modelling experiments show that 5'-Cl may compete with ATP for binding to the catalytic subunit of CDK2 and CDK4 that could lead to inhibition of these enzymes. Indeed, 5'-Cl inhibited the kinase activity of CDK2 and CDK4 both in cell free systems and in treated cells. 5'-Cl also inhibited cell cycle progression in several other tumor cell lines. Conclusion: We demonstrate the potent inhibitory effects of 5'-Cl on HL-60 cells could be mediated by arresting cells in the G0/G1 phase.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
CDK2
Indoles
CDK4
Physiology
Pyridones
Cyclin D
Antineoplastic Agents
HL-60 Cells
Cell cycle
Retinoblastoma Protein
lcsh:Physiology
lcsh:Biochemistry
Leukemia, Promyelocytic, Acute
Cyclin-dependent kinase
Catalytic Domain
Cell Line, Tumor
Humans
lcsh:QD415-436
Kinase activity
Phosphorylation
Rb
Cyclin-D
Binding Sites
biology
lcsh:QP1-981
Cyclin-dependent kinase 4
Anticancer compound
Cyclin-dependent kinase 2
Cyclin-Dependent Kinase 2
Retinoblastoma protein
Cyclin-Dependent Kinase 4
G1 Phase Cell Cycle Checkpoints
Cyclin-Dependent Kinases
Cell biology
Molecular Docking Simulation
HL-60 cell line
Pyridone-annelated isoindigo
G0/G1 phase
biology.protein
Drug Screening Assays, Antitumor
G1 phase
Subjects
Details
- Language :
- English
- ISSN :
- 14219778 and 10158987
- Volume :
- 35
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cellular Physiology and Biochemistry
- Accession number :
- edsair.doi.dedup.....e79d66c79bf92a9aa3b60c22b96defb6