Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Clinical cancer research, 2003-05, Vol.9 (5), p.1596

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2003

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.