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Advisor(s)
Abstract(s)
Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality
worldwide. Although early disease is often efficiently managed therapeutically,
available options for advanced disease are mostly ineffective. Aberrant DNA
methylation associated with gene-silencing of cancer-related genes is a common
feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive
alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine,
a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro
assays showed that hydralazine exposure led to a significant dose and time dependent
growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore,
it also induced cell cycle arrest and DNA damage. These phenotypic effects were
particularly prominent in DU145 cells. Following hydralazine exposure, decreased
levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted.
Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation
levels, with concomitant transcript re-expression, was also observed. Interestingly,
hydralazine restored androgen receptor expression, with upregulation of its target
p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor
signaling pathway is likely to be the main mechanism of hydralazine action in DU145
cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of
PCa cells, and might constitute a useful therapeutic tool.
Description
Keywords
Prostate Cancer Hydralazine DNA methyltransferases Androgen Receptor
Citation
Graça, I., Sousa, E. J., Costa-Pinheiro, P., Vieira, F. Q., Torres-Ferreira, J., Martins, M. G., Henrique, R., & Jerónimo, C. (2014). Anti-neoplastic properties of hydralazine in prostate cancer. Oncotarget, 5(15), 5950–5964. https://doi.org/10.18632/oncotarget.1909