Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy.

Abstract

PURPOSE:

The purpose of this study is to evaluate the demethylating and tumor suppressor-reactivating activity of hydralazine and procainamide.

EXPERIMENTAL DESIGN:

MDA-231, MCF-7, and T24 cell lines were treated for 5 days with 10 micro M hydralazine or 10 micro M procainamide. 5-aza-deoxycytidine at 0.75 micro M was used as positive control. BALB/c nu/nu mice xenografted with MDA-231 cells were treated with these drugs for 7 days by i.p. route. Methylation was assessed by PCR after digestion with methylation-sensitive enzymes for the ER gene and with methylation-specific PCR for retinoic acid receptor (RAR)beta and p16 genes. Gene expression was evaluated by reverse transcription-PCR and Western blot. The duration of the gene re-expressing effect of hydralazine was analyzed on T24 cells. Functionality of the re-expressed proteins was evaluated by the induction of the estrogen-responsive gene PS2 on MDA-231 cells and by the induction of G(1) arrest on T24 cells. The gene demethylating and re-expressing ability of hydralazine was tested in two patients with cervical and head and neck carcinomas, respectively.

RESULTS:

Hydralazine and procainamide induced de-methylation and re-expression of the ER, RARbeta, and p16 genes in cultured cells. Both drugs also demethylated and re-expressed the ER gene in mice. Hydralazine re-expressed the p16 gene longer as compared with 5-aza-deoxycytidine. The re-expressed genes were functional. In addition, the treatment with oral hydralazine demethylated and re-expressed the RARbeta and p16 genes in the cervical and head and cancer patients.

CONCLUSIONS:

These cardiovascular drugs have a promising tumor suppressor-reactivating action and could potentially be used in clinic as an anticancer treatment, most likely to increase the efficacy of current biological or chemotherapeutic treatments.

• Authors: Blanca Segura-Pacheco, Catalina Trejo-Becerril, Enrique Perez-Cardenas, Lucia Taja-Chayeb, Ignacio Mariscal, Alma Chavez, Carmen Acuña, Ana Maria Salazar, Marcela Lizano, Alfonso Dueñas-Gonzalez
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 5 Pg. 1596-603 (May 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12738711 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Cyclin-Dependent Kinase Inhibitor p16
• Enzyme Inhibitors
• Receptors, Estrogen
• Receptors, Retinoic Acid
• retinoic acid receptor beta
• Hydralazine
• Decitabine
• Procainamide
• Azacitidine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Azacitidine (analogs & derivatives, pharmacology)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Cycle (drug effects)
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• DNA Methylation (drug effects)
• Decitabine
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor (drug effects)
• Head and Neck Neoplasms (drug therapy)
• Humans
• Hydralazine (pharmacology)
• Mice
• Mice, Nude
• Procainamide (pharmacology)
• Receptors, Estrogen (metabolism)
• Receptors, Retinoic Acid (genetics)
• Tumor Cells, Cultured (transplantation)
• Uterine Cervical Neoplasms (drug therapy)