Inhibition of the Receptor for Advanced Glycation End Products Enhances the Cytotoxic Effect of Gemcitabine in Murine Pancreatic Tumors.

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.

• Authors: 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
• Journal: Biomolecules (Biomolecules) Vol. 11 Issue 4 (04 01 2021) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 33915939 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• HMGB1 Protein
• Microtubule-Associated Proteins
• Receptor for Advanced Glycation End Products
• Deoxycytidine
• Poly(ADP-ribose) Polymerases
• Gemcitabine

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• HMGB1 Protein (metabolism)
• Mice
• Microtubule-Associated Proteins (genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Receptor for Advanced Glycation End Products (antagonists & inhibitors, immunology, metabolism)
• Transplantation, Homologous
• Gemcitabine