Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism

The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster t...

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Bibliographic Details
Published in:	JCI insight Vol. 7; no. 22
Main Authors:	Gutierrez, Wade R, Scherer, Amanda, Rytlewski, Jeffrey D, Laverty, Emily A, Sheehan, Alexa P, McGivney, Gavin R, Brockman, Qierra R, Knepper-Adrian, Vickie, Roughton, Grace A, Quelle, Dawn E, Gordon, David J, Monga, Varun, Dodd, Rebecca D
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 22-11-2022 American Society for Clinical investigation
Subjects:	Animals Apoptosis Cell Cycle Checkpoints Cell Line, Tumor Decitabine - pharmacology Mice Oncology Sarcoma - drug therapy Oncology Drug therapy Mouse models Cancer
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Summary:	The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of DAC following treatment with the chemotherapy agent gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, DAC did not induce a robust antitumor T cell response in sarcoma. Furthermore, DAC synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces biphasic cell cycle arrest and apoptosis. Therapeutic efficacy was sequence dependent, with gemcitabine priming cells for treatment with DAC through inhibition of ribonucleotide reductase. This study identifies an apparently unique application of DAC to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising paradigm for cancer treatment by augmenting chemotherapy through addition of DAC to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.159419