Reactivation of Tumor Suppressor Genes by the Cardiovascular Drugs Hydralazine and Procainamide and Their Potential Use in Cancer Therapy

• Published in: Clinical cancer research Vol. 9; no. 5; p. 1596
• Main Authors: Segura-Pacheco, Blanca, Trejo-Becerril, Catalina, Perez-Cardenas, Enrique, Taja-Chayeb, Lucia, Mariscal, Ignacio, Chavez, Alma, Acuña, Carmen, Salazar, Ana Maria, Lizano, Marcela, Dueñas-Gonzalez, Alfonso
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.05.2003
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Cycle - drug effects; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; DNA Methylation - drug effects; 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
• ISSN: 1078-0432; 1557-3265

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 μ m hydralazine or 10 μ m procainamide. 5-aza-deoxycytidine at 0.75 μ 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 )β 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, RARβ , 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 RARβ 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.