TY - JOUR
T1 - Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms
AU - Lin, Ho Pi
AU - Kulp, Samuel K.
AU - Tseng, Ping Hui
AU - Yang, Ya Ting
AU - Yang, Chi Cheng
AU - Chen, Chang Shi
AU - Chen, Ching Shih
PY - 2004/12
Y1 - 2004/12
N2 - Evidence suggests that the angiogenic endothelium represents an important target through which celecoxib mediates in vivo antitumor effects. Nevertheless, the pharmacologic basis for celecoxib-caused growth inhibition in endothelial cells in vitro remains to be defined. Previously, we showed that celecoxib-induced apoptosis in PC-3 prostate cancer cells was mediated in part through the inhibition of 3-phosphoinositide-dependent kinase-1/Akt signaling. Our present findings show that celecoxib inhibits the growth of human umbilical vein endothelial cells (HUVEC) with pharmacologic profiles reminiscent of those of PC-3 cells. The underlying antiproliferative mechanism, however, may differ between these two cell types considering differences in the functional status of many tumor suppressors, including PTEN, p53, and retinoblastoma, all of which play integral roles in regulating cell cycle progression and survival. From a mechanistic perspective, the genomic integrity of the HUVEC system presents a vastly different intracellular context to examine how celecoxib acts to induce growth inhibition. Here, we obtain evidence that the antiproliferative effects of celecoxib and its close, cyclooxygenase-2-inactive analogue 4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl -1H-pyrazol-1-yl]benzenesulfonamide (DMC) in HUVECs at pharmacologically attainable concentrations (10-20 μmol/L) are attributable to the inhibition of phosphoinositide-dependent kinase-1/Akt signaling and cyclin-dependent kinase. Especially, celecoxib- and DMC-mediated G, arrest is associated with attenuated retinoblastoma phosphorylation through the inhibition of multiple cyclin-dependent kinases (IC50, 10-35 μmol/L). Moreover, both celecoxib and DMC reduce neovascularization in the chicken chorioallantoic membrane assay, suggesting the involvement of a cyclooxygenase-2-independent mechanism in the in vivo antiangiogenic effects of celecoxib.
AB - Evidence suggests that the angiogenic endothelium represents an important target through which celecoxib mediates in vivo antitumor effects. Nevertheless, the pharmacologic basis for celecoxib-caused growth inhibition in endothelial cells in vitro remains to be defined. Previously, we showed that celecoxib-induced apoptosis in PC-3 prostate cancer cells was mediated in part through the inhibition of 3-phosphoinositide-dependent kinase-1/Akt signaling. Our present findings show that celecoxib inhibits the growth of human umbilical vein endothelial cells (HUVEC) with pharmacologic profiles reminiscent of those of PC-3 cells. The underlying antiproliferative mechanism, however, may differ between these two cell types considering differences in the functional status of many tumor suppressors, including PTEN, p53, and retinoblastoma, all of which play integral roles in regulating cell cycle progression and survival. From a mechanistic perspective, the genomic integrity of the HUVEC system presents a vastly different intracellular context to examine how celecoxib acts to induce growth inhibition. Here, we obtain evidence that the antiproliferative effects of celecoxib and its close, cyclooxygenase-2-inactive analogue 4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl -1H-pyrazol-1-yl]benzenesulfonamide (DMC) in HUVECs at pharmacologically attainable concentrations (10-20 μmol/L) are attributable to the inhibition of phosphoinositide-dependent kinase-1/Akt signaling and cyclin-dependent kinase. Especially, celecoxib- and DMC-mediated G, arrest is associated with attenuated retinoblastoma phosphorylation through the inhibition of multiple cyclin-dependent kinases (IC50, 10-35 μmol/L). Moreover, both celecoxib and DMC reduce neovascularization in the chicken chorioallantoic membrane assay, suggesting the involvement of a cyclooxygenase-2-independent mechanism in the in vivo antiangiogenic effects of celecoxib.
UR - http://www.scopus.com/inward/record.url?scp=12344290399&partnerID=8YFLogxK
M3 - Article
C2 - 15634661
AN - SCOPUS:12344290399
SN - 1535-7163
VL - 3
SP - 1671
EP - 1680
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -
