1. Academic Validation
  2. Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism

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

  • JCI Insight. 2022 Oct 13;e159419. doi: 10.1172/jci.insight.159419.
Wade R Gutierrez 1 Amanda Scherer 1 Jeffrey D Rytlewski 1 Emily A Laverty 1 Alexa P Sheehan 1 Gavin R McGivney 1 Qierra R Brockman 1 Vickie Knepper-Adrian 1 Grace A Roughton 1 Dawn E Quelle 2 David J Gordon 3 Varun Monga 1 Rebecca D Dodd 1
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States of America.
  • 2 Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America.
  • 3 Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, United States of America.
Abstract

The DNA Methyltransferase Inhibitor decitabine has classically been used to reactivate silenced genes and as a pre-treatment for anti-cancer therapies. In a new variation of this idea, this study explores the concept of adding low-dose decitabine following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of decitabine following treatment with the chemotherapy gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, low-dose decitabine did not induce a robust anti-tumor T cell response in sarcoma. Furthermore, low-dose decitabine synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces bi-phasic cell cycle arrest and Apoptosis. Therapeutic efficacy was found to be sequence dependent, with gemcitabine priming cells for treatment with decitabine through inhibition of ribonucleotide reductase. This study identifies a unique application of low-dose decitabine to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising new paradigm for Cancer treatment by augmenting chemotherapy through addition of low-dose decitabine to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.

Keywords

Cancer; Drug therapy; Mouse models; Oncology.

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