Transient Low Doses of DNA Demethylating Agents Exert Durable Anti-tumor Effects on Hematological and Epithelial Tumor Cells
By Hsing-Chen Tsai, Huili Li, L. van Neste, Yi Cai, C. Robert, F. Rassool, James Shin, Kirsten Harbom, R. Beaty, E. Pappou and 16 more. Cancer Cell, 2012
614 citations recorded by the source corpus.
SUMMARY Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produce an anti-tumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genome-wide promoter DNA methylation, gene re-expression, and anti-tumor changes in key cellular regulatory pathways. Low dose decitabine and azacitidine may have broad applicability for cancer management.
Subfields: Cancer Research, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/29efc76dd17b5207887a955a2541d1dd942e781f
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Citations in the corpus
- Gene Body Methylation can alter Gene Expression and is a Therapeutic Target in Cancer (2014, background): “that are gradually reversed on growth in the absence of further drug treatment (Bender et al., 1999; Tsai et al., 2012).”
- Cancer epigenetics: from mechanism to therapy. (2012, background): “However, recent evidence would suggest that low doses of these agents hold the key to therapeutic benefit (Tsai et al., 2012).”
- Epigenetic Determinants of Cancer. (2016, background): “…to solid tumor models, it seems likely that at very low nanomolar doses, both Vidaza and Dacogen can “reprogram” cancer cells and cause antitumor responses, which are most likely caused by the specific targeting of DNMTs rather than producing other less off-target effects (Tsai et al. 2012).”
- Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses (2015, neutral): “Mechanisms can include reversal of abnormal promoter DNA methylation, re-expression of silenced genes including tumor suppressors (Baylin and Jones, 2011), and changes to cancer signaling pathways including apoptosis, cell-cycle activity, and stem cell functions (Tsai et al., 2012).”