Inhibition of the receptor for advanced glycation end products enhances the cytotoxic effect of gemcitabine in murine pancreatic tumors

Priyanka Swami, Kelly A. O’connell, Swetha Thiyagarajan, Ayrianne Crawford, Prathamesh Patil, Prakash Radhakrishnan, Simon Shin, Thomas C. Caffrey, James Grunkemeyer, Tammi Neville, Stefan W. Vetter, Michael A. Hollingsworth, Estelle Leclerc

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a very difficult cancer to treat. Recent in vitro and in vivo studies suggest that the activation of the receptor for advanced glycation end products (RAGE) by its ligands stimulates pancreatic cancer cell proliferation and tumor growth. Additional studies show that, in the RAGE ligand, the high mobility group box 1 (HMGB1) protein plays an important role in chemoresistance against the cytotoxic agent gemcitabine by promoting cell survival through increased autophagy. We hypothesized that blocking the RAGE/HMGB1 interaction would enhance the cytotoxic effect of gemcitabine by reducing cell survival and autophagy. Using a preclinical mouse model of PDAC and a monoclonal antibody (IgG 2A11) as a RAGE inhibitor, we demonstrate that RAGE inhibition concurrent with gemcitabine treatment enhanced the cytotoxic effect of gemcitabine. The combination of IgG 2A11 and gemcitabine resulted in decreased autophagy compared to treatment with gemcitabine combined with control antibodies. Notably, we also observed that RAGE inhibition protected against excessive weight loss during treatment with gemcitabine. Our data suggest that the combination of gemcitabine with a RAGE inhibitor could be a promising therapeutic approach for the treatment of pancreatic cancer and needs to be further investigated.

Original languageEnglish (US)
Article number526
JournalBiomolecules
Volume11
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Cachexia
  • Gemcitabine
  • Pancreatic cancer
  • RAGE

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Inhibition of the receptor for advanced glycation end products enhances the cytotoxic effect of gemcitabine in murine pancreatic tumors'. Together they form a unique fingerprint.

Cite this