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Preparation and In Vitro Characterization of Dendrimer-based Contrast Agents for Magnetic Resonance Imaging
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A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent

Manjusha Thakar1, Yue Hu1, Michael Morreale1

  • 1Department of Surgical Oncology, Johns Hopkins University, Baltimore, MD, United States of America.

Plos One
|June 22, 2018
PubMed

Insights

Epigenetic drug guadecitabine shows promise in enhancing pancreatic cancer chemotherapy. This DNA Methyltransferase 1 inhibitor improved response to Irinotecan, offering a potential new strategy for pancreatic ductal adenocarcinoma treatment.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Research

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality with limited treatment options.
  • PDAC exhibits resistance to conventional systemic chemotherapies.

Purpose of the Study:

  • To investigate the potential of epigenetic sensitization to improve chemotherapy response in PDAC.
  • To evaluate the efficacy of guadecitabine, an epigenetic modulator, in PDAC cell lines.

Main Methods:

  • PDAC cell lines were treated with varying concentrations of 5-azacitidine and guadecitabine.
  • Inhibition of DNA Methyltransferase 1 (DNMT1) expression and cell viability were assessed.
  • Guadecitabine's efficacy was evaluated with and without a delay period.
  • Sensitization with guadecitabine was tested in combination with the chemotherapeutic agent Irinotecan.

Main Results:

  • Guadecitabine effectively inhibited DNMT1 expression and reduced cell viability at nanomolar concentrations.
  • A delay period enhanced the efficacy of guadecitabine.
  • Guadecitabine-mediated sensitization significantly improved the response to Irinotecan, indicated by decreased cell viability and increased caspase activity.

Conclusions:

  • Epigenetic modulation with guadecitabine shows potential for overcoming chemotherapy resistance in PDAC.
  • Guadecitabine, particularly after a rest period, sensitizes PDAC cells to Irinotecan.
  • Further research is warranted to elucidate the precise mechanisms of action.

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