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Open Access 01-06-2006 | Review

Hydralazine target: From blood vessels to the epigenome

Authors: Claudia Arce, Blanca Segura-Pacheco, Enrique Perez-Cardenas, Lucia Taja-Chayeb, Myrna Candelaria, Alfonso Dueñnas-Gonzalez

Published in: Journal of Translational Medicine | Issue 1/2006

Abstract

Hydralazine was one of the first orally active antihypertensive drugs developed. Currently, it is used principally to treat pregnancy-associated hypertension. Hydralazine causes two types of side effects. The first type is an extension of the pharmacologic effect of the drug and includes headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness, and salt retention. The second type of side effects is caused by immunologic reactions, of which the drug-induced lupus-like syndrome is the most common, and provides clues to underscoring hydralazine's DNA demethylating property in connection with studies demonstrating the participation of DNA methylation disorders in immune diseases. Abnormalities in DNA methylation have long been associated with cancer. Despite the fact that malignant tumors show global DNA hypomethylation, regional hypermethylation as a means to silence tumor suppressor gene expression has attracted the greatest attention. Reversibility of methylation-induced gene silencing by pharmacologic means, which in turns leads to antitumor effects in experimental and clinical scenarios, has directed efforts toward developing clinically useful demethylating agents. Among these, the most widely used comprise the nucleosides 5-azacytidine and 2'deoxy-5-azacytidine; however, these agents, like current cytotoxic chemotherapy, causes myelosuppression among other side effects that could limit exploitation of their demethylating properties. Among non-nucleoside DNA demethylating drugs currently under development, the oral drug hydralazine possess the ability to reactivate tumor suppressor gene expression, which is silenced by promoter hypermethylation in vitro and in vivo. Decades of extensive hydralazine use for hypertensive disorders that demonstrated hydralazine's clinical safety and tolerability supported its testing in a phase I trial in patients with cancer, confirming its DNA demethylating activity. Hydralazine is currently being evaluated, along with histone deacetylase inhibitors either alone or as adjuncts to chemotherapy and radiation, for hematologic and solid tumors in phase II studies.

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Title: Hydralazine target: From blood vessels to the epigenome
Authors: Claudia Arce
Blanca Segura-Pacheco
Enrique Perez-Cardenas
Lucia Taja-Chayeb
Myrna Candelaria
Alfonso Dueñnas-Gonzalez
Publication date: 01-06-2006
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2006
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/1479-5876-4-10

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