Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis.

Abstract

RG7787 is a mesothelin-targeted immunotoxin designed to have low-immunogenicity, high-cytotoxic activity and fewer side effects. RG7787 kills many types of mesothelin-expressing cancer cells lines and causes tumor regressions in mice. Safety and immunogenicity of RG7787 is now being assessed in a phase I trial. To enhance the antitumor activity of RG7787, we screened for clinically used drugs that can synergize with RG7787. Actinomycin D is a potent transcription inhibitor that is used for treating several cancers. We report here that actinomycin D and RG7787 act synergistically to kill many mesothelin-positive cancer cell lines and produce major regressions of pancreatic and stomach cancer xenografts. Analyses of RNA expression show that RG7787 or actinomycin D alone and together increase levels of TNF/TNFR family members and NF-κB-regulated genes. Western blots revealed the combination changed apoptotic protein levels and enhanced cleavage of Caspases and PARP.

• Authors: Xiu Fen Liu, Laiman Xiang, Qi Zhou, Jean-Philippe Carralot, Marco Prunotto, Gerhard Niederfellner, Ira Pastan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 38 Pg. 10666-71 (09 20 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27601652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Immunoconjugates
• Immunotoxins
• Msln protein, mouse
• NF-kappa B
• Dactinomycin
• LMB-100
• Mesothelin

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dactinomycin (administration & dosage)
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Humans
• Immunoconjugates (administration & dosage)
• Immunotoxins (administration & dosage)
• Mesothelin
• Mice
• NF-kappa B (genetics)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Xenograft Model Antitumor Assays