RT Journal Article
SR Electronic
T1 MJ-29 Inhibits Tubulin Polymerization, Induces Mitotic Arrest, and Triggers Apoptosis via Cyclin-Dependent Kinase 1-Mediated Bcl-2 Phosphorylation in Human Leukemia U937 Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 477
OP 488
DO 10.1124/jpet.109.165415
VO 334
IS 2
A1 Jai-Sing Yang
A1 Mann-Jen Hour
A1 Wen-Wen Huang
A1 Kuei-Li Lin
A1 Sheng-Chu Kuo
A1 Jing-Gung Chung
YR 2010
UL http://jpet.aspetjournals.org/content/334/2/477.abstract
AB We investigated the signaling pathways associated with microtubule interaction and apoptosis in U937 cells in vitro and in the U937 xenograft model in vivo by using 6-pyrrolidinyl-2-(2-hydroxyphenyl)-4-quinazolinone (MJ-29). MJ-29 induced growth inhibition and cell death of leukemia cell lines (U937, HL-60, K562, and KG-1) in a dose- and time-dependent manner but did not obviously impair the viability of normal cells (peripheral blood mononuclear cells and human umbilical vein endothelial cells). MJ-29 interacted with α- and β-tubulin, inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. MJ-29 caused mitotic arrest by activating cyclin-dependent kinase 1 (CDK1)/cyclin B complex activity. MJ-29-induced growth inhibition and activation of CDK1 activity were significantly attenuated by roscovitine (CDK inhibitor) and CDK1 small interfering RNA (siRNA). Furthermore, MJ-29-induced Bcl-2 phosphorylation was also significantly attenuated by CDK1 siRNA. MJ-29 caused an increase in the protein levels of cytosolic cytochrome c, apoptotic protease-activating factor-1, procaspase-9, and apoptosis-inducing factor. MJ-29-promoted activation of caspase-9 and caspase-3 during apoptosis was significantly attenuated by caspase-9 and caspase-3 inhibitors. It is noteworthy that in BALB/cnu/nu mice bearing U937 xenograft tumors MJ-29 inhibited tumor growth in vivo. The terminal deoxynucleotidyl transferase-mediated d-UTP nick end-labeling-positive apoptotic cells of tumor sections significantly increased in MJ-29-treated mice compared with the control group. In conclusion, our results suggest that MJ-29 induces mitotic arrest and apoptosis in U937 cells via CDK1-mediated Bcl-2 phosphorylation and inhibits the in vivo tumor growth of U937 xenograft mice.