Abstract
Gemcitabine is a cytotoxic cytidine analog, which is widely used in anti-cancer therapy. One mechanism by which gemcitabine acts is by inhibiting nucleotide excision repair (NER). Recently NER was implicated in Gadd45 mediated DNA demethylation and epigenetic gene activation. Here we analyzed the effect of gemcitabine on DNA demethylation. We find that gemcitabine inhibits specifically Gadd45a mediated reporter gene activation and DNA demethylation, similar to the topoisomerase I inhibitor camptothecin, which also inhibits NER. In contrast, base excision repair inhibitors had no effect on DNA demethylation. In Xenopus oocytes, gemcitabine inhibits DNA repair synthesis accompanying demethylation of oct4. In mammalian cells, gemcitabine induces DNA hypermethylation and silencing of MLH1. The results indicate that gemcitabine induces epigenetic gene silencing by inhibiting repair mediated DNA demethylation. Thus, gemcitabine can function epigenetically and provides a tool to manipulate DNA methylation.
Highlights
Gemcitabine (29deoxy-2929-difluorocytidine monohydrochloride, GEMZAR) is one of the most widely used anti-cancer drugs and is effective against solid tumors [1]
Pioneering work from the Plunkett laboratory showed that gemcitabine is a pro-drug, which after intracellular uptake is metabolized to gemcitabine diphosphate and triphosphate, whose incorporation into DNA results in chain termination by inhibiting DNA polymerase activity [2,3]
We showed that Growth Arrest and DNA Damage inducible protein 45 a (Gadd45a) is a key mediator of active DNA demethylation [13]
Summary
Gemcitabine (29deoxy-2929-difluorocytidine monohydrochloride, GEMZAR) is one of the most widely used anti-cancer drugs and is effective against solid tumors [1]. We tested this possibility and find that gemcitabine inhibits Gadd45a mediated reporter gene activation. Gemcitabine inhibits unscheduled DNA synthesis in methylated oct4 plasmid in Xenopus oocytes.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
