Promoter methylation status of VEGF receptor genes-a possible epigenetic biomarker to anticipate the efficacy of intracellular-acting vegf-targeted drugs in cancer cells

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Title
Promoter methylation status of VEGF receptor genes-a possible epigenetic biomarker to anticipate the efficacy of intracellular-acting vegf-targeted drugs in cancer cells
Author(s)
J Kim; J Hwang; H Jeong; H J Song; J Shin; G Hur; Young Woo Park; S H Lee; J Kim
Bibliographic Citation
Epigenetics, vol. 7, no. 2, pp. 191-200
Publication Year
2012
Abstract
We evaluated whether the inhibitory effects of vascular endothelial growth factor (VEGF)-targeted drugs on the proliferation of cancer cells differed according to VEGF receptor (VEGFR) genes, Flt1 and KDR, promoter methylation status. Five hyper-VEGFR-methylation and six no-VEGFR-methylation cancer cells were used for the present study, together with human umbilical endothelial cells (HUVECs) as a control. No-VEGFR-methylation cancer cells showed higher expression of Flt1 and KDR than hyper-VEGFR-methylation cancer cells. Hyper-VEGFR-methylation cancer cells only showed increased expression and protein levels of Flt1 and KDR after treatment with the de methylase 5-aza-2'-deoxycytidine. Two drugs (a VEGF-specific-antibody, bevacizumab and a KDR-specific-antibody) targeting extracellular VEGF-VEGFR signaling and two VEGF-specific-tyrosine kinase inhibitors (PTK/ZK and sunitinib) targeting intracellular VEGFR signaling were used in the cell proliferation assay. HUVECs showed dose- and time-dependent proliferation decrease with all tested drugs over a 72 h incubation period. No- or hyper-VEGFR-methylation cancer cells showed no significant proliferation diferences after treatment with VEGF-specific-antibody or VEGFR2-specific-antibody. After PTK/ZK or sunitinib treatment, no-VEGFR-methylation cancer cells showed dose- or time-dependent decreases in proliferation. Hyper-VEGFR-methylation cancer cells also showed proliferation inhibition by VEGF-specific-tyrosine kinase inhibitors after de methylation of Flt1 and KDR. Proliferation inhibition synergistically increased after combination of de methylation with PTK/ZK in hyper-VEGF-methylation cancer cells. We observed that intracellular targeting of VEGF-VEGFR signaling could be more effective than extracellular targeting of the pathway in the suppression of proliferation of some cancer cells. In particular, the efficacy of intracellular targeting of VEGF-specific-tyrosine kinase inhibitors might be influenced by the epigenetic alteration of VEGFRs.
Keyword
Epigenetic changeFlt1KDRPromoter hypermethylationVascular endothelial growth factor (VEGF)VEGF receptor (VEGFR)VEGF-specific antibodyVEGF-specific tyrosine kinase inhibitorVEGF-targeted drugVEGFR2-specific antibody
ISSN
1559-2294
Publisher
T&F (Taylor & Francis)
DOI
http://dx.doi.org/10.4161/epi.7.2.18973
Type
Article
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1. Journal Articles > Journal Articles
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