S110 a 5-aza-2’-deoxycytidine-containing dinucleotide is an effective DNA methylation inhibitor in vivo and can reduce tumor growth

摘要

Methylation of CpG islands in promoter regions is often associated with gene silencing and aberrant DNA methylation occurs in most cancers, leading to the silencing of some tumor suppressor genes. Reversal of this abnormal hypermethylation by DNA methylation inhibitors is effective in re-activating methylation-silenced tumor-suppressor genes both in vitro and in vivo. Several DNA methylation inhibitors have been well studied; the most potent among them is 5-aza-2’-deoxycytidine (5-Aza-CdR), but it can induce myelosuppression in patients. S110 is a dinucleotide consisting of 5-Aza-CdR followed by a deoxyguanosine which we previously showed to be effective in vitro as a DNA methylation inhibitor while being less prone to deamination by cytidine deaminase, making it a promising alternative to 5-Aza-CdR. Here we show that S110 is better tolerated than 5-Aza-CdR in mice, and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding tumor growth in human xenograft. We also demonstrate that S110 is effective by both intraperitoneal (IP) and subcutaneous (SQ) deliveries. S110 therefore is a promising new agent that acts similarly to 5-Aza-CdR and has better stability and less toxicity.