Synergistic antineoplastic action of DNA methylation inhibitor 5‐AZA‐2′‐deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells

• Published in: International journal of cancer 2003-01, Vol.103 (2), p.177-184
• Main Authors: Primeau, Mélanie, Gagnon, Jacynthe, Momparler, Richard L.
• Format: Article
• Language: English
• Subjects: 5‐aza‐2′‐deoxycytydine; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; depsipeptide; DNA methylation; DNA Methylation - drug effects; DNA Primers - chemistry; Drug Combinations; Drug Synergism; Enzyme Inhibitors - pharmacology; Female; gelsolin; Gelsolin - genetics; Gelsolin - metabolism; Gene Expression Regulation, Neoplastic; Gene Silencing; General aspects; Genes, Tumor Suppressor; Histone Deacetylase Inhibitors; histone deacetylation; Humans; In Vitro Techniques; maspin; Medical sciences; Pharmacology. Drug treatments; Proteins - genetics; Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Serpins - genetics; Serpins - metabolism; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.10789

During tumorigenesis, cancer‐related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5‐aza‐2′‐deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5‐aza‐2′‐deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA‐MB‐231 and MDA‐MB‐435 human breast carcinoma cell lines. We observed that the combination of 5‐aza‐2′‐deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi‐quantitative RT‐PCR, we observed that 5‐aza‐2′‐deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5‐aza‐2′‐deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer. © 2002 Wiley‐Liss, Inc.