Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms

Ho Pi Lin, Samuel K. Kulp, Ping Hui Tseng, Ya Ting Yang, Chi Cheng Yang, Chang Shi Chen, Ching Shih Chen

研究成果: Article同行評審

57 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)1671-1680
頁數10
期刊Molecular cancer therapeutics
3
發行號12
出版狀態Published - 2004 十二月

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究

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