期刊
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
卷 35, 期 5, 页码 1943-1957出版社
KARGER
DOI: 10.1159/000374003
关键词
Pyridone-annelated isoindigo; Anticancer compound; Cell cycle; G0/G1 phase; Cyclin-D; CDK2; CDK4; Rb; Kinase activity; HL-60 cell line
资金
- King Abdulaziz City for Science and Technology (KACST, Riyadh, Kingdom of Saudi Arabia) [AT-34-136]
- Scientific Research Support Fund (SRSF, Amman, Jordan) [mph/1/6/2011]
- King Abdullah International Medical Research Center (KAIMRC) in Riyadh, Saudi Arabia
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. Copyright (C) 2015 S. Karger AG, Basel
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