Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines.
BACKGROUND
Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines.


RESULTS
Hydralazine showed no growth inhibitory effect on cervical, colon, breast, sarcoma, glioma, and head & neck cancer cell lines when used alone. On the contrary, valproic acid showed a strong growth inhibitory effect that is potentiated by hydralazine in some cell lines. Individually, hydralazine and valproic acid displayed distinctive effects upon global gene over-expression but the number of genes over-expressed increased when cells were treated with the combination. Treatment of HeLa cells with hydralazine and valproic acid lead to an increase in the cytotoxicity of gemcitabine, cisplatin and adriamycin. A higher antitumor effect of adriamycin was observed in mice xenografted with human fibrosarcoma cells when the animals were co-treated with hydralazine and valproic acid.


CONCLUSIONS
Hydralazine and valproic acid, two widely used drugs for cardiovascular and neurological conditions respectively have promising antineoplastic effects when used concurrently and may increase the antitumor efficacy of current cytotoxic agents.
Chavez-Blanco
Alma
A
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Perez-Plasencia
Carlos
C
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Perez-Cardenas
Enrique
E
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Carrasco-Legleu
Claudia
C
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Rangel-Lopez
Edgar
E
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Segura-Pacheco
Blanca
B
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Taja-Chayeb
Lucia
L
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Trejo-Becerril
Catalina
C
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Gonzalez-Fierro
Aurora
A
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Candelaria
Myrna
M
Division of Clinical Research, Instituto Nacional de Cancerología, Mexico City, Mexico.
Cabrera
Gustavo
G
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.
Duenas-Gonzalez
Alfonso
A
Unidad de Investigación Biomédica en Cancer. Instituto de Investigaciones Biomédicas, UNAM, /Instituto Nacional de Cancerología, Mexico City, Mexico.