Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer

Rouzbeh Daylami, Diego J. Muilenburg, Subbulakshmi Virudachalam, Richard J Bold

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Background: Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena. Methods: We examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined. Results: Combination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2. Conclusion: The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.

Original languageEnglish (US)
Article number102
JournalJournal of Experimental and Clinical Cancer Research
Volume33
Issue number1
DOIs
StatePublished - 2014

Keywords

  • Gemcitabine
  • Pancreatic cancer
  • PEG-ADI
  • RRM2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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