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- W1445879316 abstract "693 Despite their clinical activity in the treatment of myelodysplastic syndrome and acute myeloid leukemia, the precise mechanism behind the clinical efficacy of DNA methyltransferase (DNMT) inhibitors is not clear. Mechanisms beyond DNMT inhibition and gene re-expression may be required for clinical response. In this study, we evaluated the possible genotoxic effects of the DNMT inhibitor decitabine in leukemia cell lines. Decitabine induced DNA damage in ML-1, BV-173, KG-1a (p53 mutated) and HL-60 (p53 null) leukemia cells as indicated by the double strand break (DSB) marker γ-H2AX. Decitabine induced G2/M cell cycle arrest for 24 or 48 h followed by apoptosis in the four cell lines, regardless of their p53 status. To further investigate the role of p53 in decitabine-induced apoptosis, pretreatment of p53-wild type cells (ML-1 and BV-173) with pifithrin-α (p53 transactivation inhibitor) did not significantly decrease decitabine-induced apoptosis but did inhibit apoptosis in response to cytarabine. Moreover, nutlin-3a (MDM2 inhibitor) did not enhance decitabine-induced apoptosis but did enhance cytarabine-induced apoptosis, further confirming the dispensable role of p53 in decitabine-induced apoptosis. ROS are known inducers of DNA damage. Decitabine treatment generated ROS in the 4 cell lines; however, γ-H2AX induction was insensitive to the ROS scavenger N-acetyl-L-cysteine (NAC), indicating that DNA damage by decitabine is ROS-independent. ROS generation can induce apoptosis in caspase-dependent or -independent manner. NAC treatment partially inhibited decitabine-induced apoptosis, indicating that ROS generation is not the only apoptosis initiator. Inhibition of caspases activity by the pan-caspase inhibitor Z-VAD-FMK also partially inhibited decitabine-induced apoptosis, suggesting the involvement of other factors in addition to caspases in decitabine-induced apoptosis. The role of ROS generation in caspase activation requires further investigation. Our data demonstrate that decitabine can induce DNA damage in a ROS-independent manner and apoptosis in a p53-independent manner through both ROS production and caspase activation." @default.
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- W1445879316 date "2007-05-01" @default.
- W1445879316 modified "2023-09-23" @default.
- W1445879316 title "Decitabine-induced apoptosis is p53-independent and mediated through reactive oxygen species (ROS) production and caspase activation" @default.
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