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

Wade R Gutierrez; Amanda Scherer; Jeffrey D Rytlewski; Emily A Laverty; Alexa P Sheehan; Gavin R McGivney; Qierra R Brockman; Vickie Knepper-Adrian; Grace A Roughton; Dawn E Quelle; David J Gordon; Varun Monga; Rebecca D Dodd

doi:10.1172/jci.insight.159419

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

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

Wade R Gutierrez, Amanda Scherer, Jeffrey D Rytlewski, Emily A Laverty, Alexa P Sheehan, Gavin R McGivney, Qierra R Brockman, Vickie Knepper-Adrian, Grace A Roughton, Dawn E Quelle, …

JCI insight, Vol.7(22), e159419

10/13/2022

DOI: 10.1172/jci.insight.159419

PMCID: PMC9746804

PMID: 36227698

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Abstract

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.

Details

Title: Subtitle: Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism
Creators: Wade R Gutierrez
Amanda Scherer
Jeffrey D Rytlewski
Emily A Laverty
Alexa P Sheehan
Gavin R McGivney
Qierra R Brockman
Vickie Knepper-Adrian
Grace A Roughton
Dawn E Quelle
David J Gordon
Varun Monga
Rebecca D Dodd
Resource Type: Journal article
Publication Details: JCI insight, Vol.7(22), e159419
DOI: 10.1172/jci.insight.159419
PMID: 36227698
PMCID: PMC9746804
NLM abbreviation: JCI Insight
ISSN: 2379-3708
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: T32 GM067795, T32 GM007337; DOI: 10.13039/100000054, name: National Cancer Institute, award: P30 CA086862; DOI: 10.13039/100000048, name: American Cancer Society, award: 134038-RSG-19-198-01
Language: English
Date published: 10/13/2022
Academic Unit: Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Hematology/Oncology; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984305984102771

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