Hydralazine target: From blood vessels to the epigenome

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.

Molecular Modeling and Molecular Dynamics Studies of Hydralazine with Human DNA Methyltransferase 1

“…[19,40,41] This suggests that hydralazine is a comparably weak inhibitor of DNA methyltransferases that can show increased inhibitory potency under certain experimental conditions. Consistent with this notion, the predicted free energy of binding for hydralazine appeared less favorable than that of nucleoside analogues and other non-nucleoside demethylating drugs.…”

“…Alternative DNMT inhibitors include the known drugs procainamide, procaine, and hydralazine, which are commonly used as antiarrhythmic, local anesthetic, and antihypertensive drugs, respectively (Figure 2). [19] Additional DNMT inhibitors are the polyphenol compound from green tea extract, (À)-epigallocatechin-3-gallate (EGCG) [20] and RG108, which was discovered by a docking-based virtual screening methodology based on a homology model of human DNMT1. [21] A binding model of EGCG within the catalytic domain of DNMT1 has also been proposed.…”

Wnt Signaling in Renal Cancer

“…Of greater interest in this review are demethylating agents, because of the relevance that silencing of tumor suppressor genes through CpG island hypermethylation has on kidney cancer. Many agents targeting hypermethylation are in clinical or preclinical studies (reviewed in [127]). …”

Clinical applications of epigenetics in cardiovascular disease: the long road ahead

“…88,89 Some examples of common drugs with newly discovered epigenetic effects are vasodilators such as hydralazine, which has been shown to inhibit DNA methylation by either interfering with DNA methyltransferase directly or by reducing its gene expression, and procainamide, a sodium channel blocker that inhibits DNA methyltransferase I. 90-92 A serious side effect common to both hydralazine and procainamide is an autoimmune disease similar to lupus, believed to be triggered by extensive hypomethylation across the genome. 90,93 Both of these therapeutic approaches are now considered a promising avenue for treating cancer, 94 but the cardiovascular implications of their epigenetic effects remain unclear.…”

“…90-92 A serious side effect common to both hydralazine and procainamide is an autoimmune disease similar to lupus, believed to be triggered by extensive hypomethylation across the genome. 90,93 Both of these therapeutic approaches are now considered a promising avenue for treating cancer, 94 but the cardiovascular implications of their epigenetic effects remain unclear.…”