- 作者: Yi-Shiuan Lin; Arthur Y. Shaw; Shi-Gang Wang; Chia-Chen Hsu; I-Wen Teng; Min-Jen Tseng; Tim H.-M. Huang; Ching-Shih Chen; Yu-Wei Leu; Shu-Huei Hsiao
- 作者服務機構: Human Epigenomics Center, Department of Life Science, Institute of Molecular Biology and Institute of Biomedical Science, National Chung Cheng University, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background: Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer
treatment as demonstrated by the US Food and Drug Administration approval of the DNA
methyltransferase inhibitors azacytidine and 5-aza-2’-deoxycytidine for the treatment of
myelodysplastic syndromes. But their use is associated with increased incidences of bone
marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating
agent for clinical translation. While procainamide is much safer than 5-aza-2’-deoxycytidine, it
requires high concentrations to be effective in DNA demethylation in suppressing cancer cell
growth. Thus, our laboratories have embarked on the pharmacological exploitation of
procainamide to develop potent DNA methylation inhibitors through lead optimization.
Methods: We report the use of a DNA methylation two-component enhanced green fluorescent protein
reporter system as a screening platform to identify novel DNA methylation inhibitors from a
compound library containing procainamide derivatives.
Results: A lead agent IM25, which exhibits substantially higher potency in GSTp1 DNA demethylation
with lower cytotoxicity in MCF7 cells relative to procainamide and 5-aza-2’-deoxycytidine, was identified by the screening platform.
Conclusions: Our data provide a proof-of-concept that procainamide could be pharmacologically exploited to
develop novel DNA methylation inhibitors, of which the translational potential in cancer
therapy/prevention is currently under investigation. - 中文關鍵字: --
- 英文關鍵字: --