Abstract:
:2-Phenyl-4-quinolone series compounds have exhibited growth inhibitory influence on several human cancer cell lines. In this study, we investigated the effects of 2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (Smh-3) on viability, cell cycle and apoptotic cell death which occurred in different leukemia cell lines (HL-60, U937 and K562) in a dose- and time-dependent manner, but which did not obviously impair the viability of normal human umbilical vein endothelial cells (HUVEC) in vitro. The approximate IC50 was 103.26 ± 4.59 nM for a 48 h treatment in HL-60 cells. Cell cycle analysis showed that 100 nM Smh-3 induced signi-ficant G2/M arrest in examined cells. Within 0, 12, 24 and 48 h of treatment, Smh-3 inhibited CDK1 activity and decreased protein levels of CDK1, cyclin A and cyclin B. Smh-3-induced chromatin condensation and DNA fragmentation were determined by DAPI and TUNEL staining. Cell apoptosis was significantly reduced after pretreatment with a pan-caspase inhibitor (Z-VAD-fmk) and results indicated that Smh-3-induced apoptosis was mainly mediated by activation of the caspase cascade in HL-60 cells. Results from colorimetric assays and Western blot analysis indicated that activities of caspase-9, -7 and -3 were promoted in Smh-3-treated HL-60 cells during cell apoptosis. Smh-3-induced apoptosis in HL-60 cells was accompanied by an apparent increase in ROS production, and protein levels of cytosolic cytochrome c, apoptotic protease activating factor-1 (Apaf-1) and apoptosis-inducing factor (AIF). Strikingly, Smh-3 induced apoptosis in HL-60 cells by simultaneously suppressing protein levels of AKT, p-AKT, p-mTOR and p-BAD and inducing BAD protein levels. Taken together, we conclude that Smh-3 acts against leukemia cells in vitro via G2/M phase arrest, down-regulation of AKT activity and induction of mitochondrial-dependent apoptotic pathways.
journal_name
Int J Oncoljournal_title
International journal of oncologyauthors
Huang SM,Yang JS,Tsai SC,Chen MH,Hsu MH,Lin HY,Chou LC,Chinag JH,Lee KH,Huang LJ,Kuo SCdoi
10.3892/ijo.2011.952subject
Has Abstractpub_date
2011-05-01 00:00:00pages
1357-64issue
5eissn
1019-6439issn
1791-2423journal_volume
38pub_type
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