DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors.

ABSTRACT: Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene deletion/disruption (DNMT1^-/-) on anticancer activity of a class of DNMTi in vitro, in vivo and in human cancers. The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. The drugs induced DNA damage that concurred with DNMT1 inhibition, subsequent G₂/M cell-cycle arrest and apoptosis, and upregulated p21 in DNMT1^+/+ versus DNMT1^-/- status, with aza-T-dCyd the most potent. Tumor growth and DNMT1 were significantly inhibited, and p21 was upmodulated in mice be

SUBMITTER: Laranjeira ABA 

PROVIDER: S-EPMC10097729 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature