Anti-neoplastic properties of hydralazine in prostate cancer
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Inês Graça1,4, Elsa J Sousa1, Pedro Costa-Pinheiro1, Filipa Q Vieira1,4, Jorge Torres-Ferreira1,2, Maria Gabriela Martins 3, Rui Henrique1,2,5, Carmen Jerónimo1,5
1 Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto,
2 Department of Pathology, Portuguese Oncology Institute-Porto,
3 Department of Hematology - Laboratory of Flow Cytometry, Portuguese Oncology Institute-Porto,
4 Departments of School of Allied Health Sciences ESTSP, Polytechnic of Porto,
5 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto
Carmen Jerónimo, email:
Keywords: Prostate Cancer, Hydralazine, DNA methyltransferases, Androgen Receptor
Received: February 14, 2014 Accepted: April 16, 2014 Published: April 17, 2014
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.
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