The novel synthesized 2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (Smh-3) compound induces G2/M phase arrest and mitochondrial-dependent apoptotic cell death through inhibition of CDK1 and AKT activity in HL-60 human leukemia cells

  • Authors:
    • Shih-Ming Huang
    • Jai-Sing Yang
    • Shih-Chang Tsai
    • Ming-Hua Chen
    • Mei-Hua Hsu
    • Hui-Yi Lin
    • Li-Chen Chou
    • Jo-Hua Chinag
    • Kuo-Hsiung Lee
    • Li-Jiau Huang
    • Sheng-Chu Kuo
  • View Affiliations

  • Published online on: February 22, 2011     https://doi.org/10.3892/ijo.2011.952
  • Pages: 1357-1364
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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 signi­ficant 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.

Related Articles

Journal Cover

May 2011
Volume 38 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
APA
Huang, S., Yang, J., Tsai, S., Chen, M., Hsu, M., Lin, H. ... Kuo, S. (2011). The novel synthesized 2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (Smh-3) compound induces G2/M phase arrest and mitochondrial-dependent apoptotic cell death through inhibition of CDK1 and AKT activity in HL-60 human leukemia cells. International Journal of Oncology, 38, 1357-1364. https://doi.org/10.3892/ijo.2011.952
MLA
Huang, S., Yang, J., Tsai, S., Chen, M., Hsu, M., Lin, H., Chou, L., Chinag, J., Lee, K., Huang, L., Kuo, S."The novel synthesized 2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (Smh-3) compound induces G2/M phase arrest and mitochondrial-dependent apoptotic cell death through inhibition of CDK1 and AKT activity in HL-60 human leukemia cells". International Journal of Oncology 38.5 (2011): 1357-1364.
Chicago
Huang, S., Yang, J., Tsai, S., Chen, M., Hsu, M., Lin, H., Chou, L., Chinag, J., Lee, K., Huang, L., Kuo, S."The novel synthesized 2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (Smh-3) compound induces G2/M phase arrest and mitochondrial-dependent apoptotic cell death through inhibition of CDK1 and AKT activity in HL-60 human leukemia cells". International Journal of Oncology 38, no. 5 (2011): 1357-1364. https://doi.org/10.3892/ijo.2011.952