40 Citations (Scopus)

Abstract

This study was designed to investigate the effect of YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, in human umbilical vein endothelial cells (HUVECs) proliferation and its underlying mechanism. YC-1 at a range of concentrations (5-50μM) inhibited DNA synthesis and decreased cell number in cultured HUVEC in a dose- and time-dependent manner. YC-1 was not cytotoxic at these concentrations. [3H]thymidine incorporation and flow cytometry analyses revealed that YC-1 treatment decreased DNA synthesis and arrested the cells at the G0/G1 phase of the cell cycle. Western blot analysis demonstrated that YC-1 (5-50μM) increased the levels of cyclin-dependent kinase (CDK)-inhibitory proteins (CKIs), p21 and p27, but did not induce any significant changes of cyclins and CDKs. In the YC-1-treated HUVEC, the formation of CDK2-p21 complex, but not CDK2-p27 complex, was increased and the assayable CDK2 kinase activity was decreased. These changes were in a dose-dependent manner. In contrast, the formations of CDK4-p21 and CDK4-p27 complex were slightly increased and the assayable CDK4 kinase activity was slightly decreased (if there were any changes). Pretreatment with guanylyl cyclase inhibitors, 1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ) and methylene blue, inhibited the YC-1-induced increase of cyclic GMP level, but did not change significantly the magnitude of the YC-1-induced inhibition of thymidine incorporation and cell number in HUVEC. These results indicate that YC-1-induced cell cycle arrest in HUVEC occurred when the cyclin-CDK system was inhibited just as p21 and p27 protein levels were augmented. This YC-1-induced antiproliferation effect in HUVEC is via a cyclic GMP-independent pathway.

Original languageEnglish
Pages (from-to)263-271
Number of pages9
JournalBiochemical Pharmacology
Volume66
Issue number2
DOIs
Publication statusPublished - Jul 15 2003

Fingerprint

Cyclic GMP
Endothelial cells
Human Umbilical Vein Endothelial Cells
Endothelial Cells
Cyclins
Cyclin-Dependent Kinases
Thymidine
Cyclin-Dependent Kinase Inhibitor Proteins
Phosphotransferases
Cell Count
Cells
Cell Cycle Resting Phase
Flow cytometry
Guanylate Cyclase
Methylene Blue
DNA
Cell proliferation
G1 Phase
Cell Cycle Checkpoints
Cell Cycle

Keywords

  • Cyclic GMP
  • Cyclin
  • Endothelial cells
  • p21
  • p27
  • YC-1

ASJC Scopus subject areas

  • Pharmacology

Cite this

YC-1 inhibits proliferation of human vascular endothelial cells through a cyclic GMP-independent pathway. / Hsu, Hun Kung; Juan, Shu Hui; Ho, Pei Yin; Liang, Yu Chih; Lin, Chien-Huang; Teng, Che Ming; Lee, Wen Sen.

In: Biochemical Pharmacology, Vol. 66, No. 2, 15.07.2003, p. 263-271.

Research output: Contribution to journalArticle

@article{cc0c391c6e734b799975ac1b0ae04834,
title = "YC-1 inhibits proliferation of human vascular endothelial cells through a cyclic GMP-independent pathway",
abstract = "This study was designed to investigate the effect of YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, in human umbilical vein endothelial cells (HUVECs) proliferation and its underlying mechanism. YC-1 at a range of concentrations (5-50μM) inhibited DNA synthesis and decreased cell number in cultured HUVEC in a dose- and time-dependent manner. YC-1 was not cytotoxic at these concentrations. [3H]thymidine incorporation and flow cytometry analyses revealed that YC-1 treatment decreased DNA synthesis and arrested the cells at the G0/G1 phase of the cell cycle. Western blot analysis demonstrated that YC-1 (5-50μM) increased the levels of cyclin-dependent kinase (CDK)-inhibitory proteins (CKIs), p21 and p27, but did not induce any significant changes of cyclins and CDKs. In the YC-1-treated HUVEC, the formation of CDK2-p21 complex, but not CDK2-p27 complex, was increased and the assayable CDK2 kinase activity was decreased. These changes were in a dose-dependent manner. In contrast, the formations of CDK4-p21 and CDK4-p27 complex were slightly increased and the assayable CDK4 kinase activity was slightly decreased (if there were any changes). Pretreatment with guanylyl cyclase inhibitors, 1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ) and methylene blue, inhibited the YC-1-induced increase of cyclic GMP level, but did not change significantly the magnitude of the YC-1-induced inhibition of thymidine incorporation and cell number in HUVEC. These results indicate that YC-1-induced cell cycle arrest in HUVEC occurred when the cyclin-CDK system was inhibited just as p21 and p27 protein levels were augmented. This YC-1-induced antiproliferation effect in HUVEC is via a cyclic GMP-independent pathway.",
keywords = "Cyclic GMP, Cyclin, Endothelial cells, p21, p27, YC-1",
author = "Hsu, {Hun Kung} and Juan, {Shu Hui} and Ho, {Pei Yin} and Liang, {Yu Chih} and Chien-Huang Lin and Teng, {Che Ming} and Lee, {Wen Sen}",
year = "2003",
month = "7",
day = "15",
doi = "10.1016/S0006-2952(03)00244-2",
language = "English",
volume = "66",
pages = "263--271",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - YC-1 inhibits proliferation of human vascular endothelial cells through a cyclic GMP-independent pathway

AU - Hsu, Hun Kung

AU - Juan, Shu Hui

AU - Ho, Pei Yin

AU - Liang, Yu Chih

AU - Lin, Chien-Huang

AU - Teng, Che Ming

AU - Lee, Wen Sen

PY - 2003/7/15

Y1 - 2003/7/15

N2 - This study was designed to investigate the effect of YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, in human umbilical vein endothelial cells (HUVECs) proliferation and its underlying mechanism. YC-1 at a range of concentrations (5-50μM) inhibited DNA synthesis and decreased cell number in cultured HUVEC in a dose- and time-dependent manner. YC-1 was not cytotoxic at these concentrations. [3H]thymidine incorporation and flow cytometry analyses revealed that YC-1 treatment decreased DNA synthesis and arrested the cells at the G0/G1 phase of the cell cycle. Western blot analysis demonstrated that YC-1 (5-50μM) increased the levels of cyclin-dependent kinase (CDK)-inhibitory proteins (CKIs), p21 and p27, but did not induce any significant changes of cyclins and CDKs. In the YC-1-treated HUVEC, the formation of CDK2-p21 complex, but not CDK2-p27 complex, was increased and the assayable CDK2 kinase activity was decreased. These changes were in a dose-dependent manner. In contrast, the formations of CDK4-p21 and CDK4-p27 complex were slightly increased and the assayable CDK4 kinase activity was slightly decreased (if there were any changes). Pretreatment with guanylyl cyclase inhibitors, 1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ) and methylene blue, inhibited the YC-1-induced increase of cyclic GMP level, but did not change significantly the magnitude of the YC-1-induced inhibition of thymidine incorporation and cell number in HUVEC. These results indicate that YC-1-induced cell cycle arrest in HUVEC occurred when the cyclin-CDK system was inhibited just as p21 and p27 protein levels were augmented. This YC-1-induced antiproliferation effect in HUVEC is via a cyclic GMP-independent pathway.

AB - This study was designed to investigate the effect of YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole, in human umbilical vein endothelial cells (HUVECs) proliferation and its underlying mechanism. YC-1 at a range of concentrations (5-50μM) inhibited DNA synthesis and decreased cell number in cultured HUVEC in a dose- and time-dependent manner. YC-1 was not cytotoxic at these concentrations. [3H]thymidine incorporation and flow cytometry analyses revealed that YC-1 treatment decreased DNA synthesis and arrested the cells at the G0/G1 phase of the cell cycle. Western blot analysis demonstrated that YC-1 (5-50μM) increased the levels of cyclin-dependent kinase (CDK)-inhibitory proteins (CKIs), p21 and p27, but did not induce any significant changes of cyclins and CDKs. In the YC-1-treated HUVEC, the formation of CDK2-p21 complex, but not CDK2-p27 complex, was increased and the assayable CDK2 kinase activity was decreased. These changes were in a dose-dependent manner. In contrast, the formations of CDK4-p21 and CDK4-p27 complex were slightly increased and the assayable CDK4 kinase activity was slightly decreased (if there were any changes). Pretreatment with guanylyl cyclase inhibitors, 1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ) and methylene blue, inhibited the YC-1-induced increase of cyclic GMP level, but did not change significantly the magnitude of the YC-1-induced inhibition of thymidine incorporation and cell number in HUVEC. These results indicate that YC-1-induced cell cycle arrest in HUVEC occurred when the cyclin-CDK system was inhibited just as p21 and p27 protein levels were augmented. This YC-1-induced antiproliferation effect in HUVEC is via a cyclic GMP-independent pathway.

KW - Cyclic GMP

KW - Cyclin

KW - Endothelial cells

KW - p21

KW - p27

KW - YC-1

UR - http://www.scopus.com/inward/record.url?scp=0038771261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038771261&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(03)00244-2

DO - 10.1016/S0006-2952(03)00244-2

M3 - Article

VL - 66

SP - 263

EP - 271

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 2

ER -