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

  • Segura-Pacheco B
  • Trejo-Becerril C
  • Perez-Cardenas E
 et al. 
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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 G1 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, RAR{beta}, 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 RAR{beta} 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.

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Authors

  • Blanca Segura-Pacheco

  • Catalina Trejo-Becerril

  • Enrique Perez-Cardenas

  • Lucia Taja-Chayeb

  • Ignacio Mariscal

  • Alma Chavez

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