Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis.
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.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Xiu Fen
XF
Liu
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Laiman
L
Xiang
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Qi
Q
Zhou
Office of Innovation, Hoffman-La Roche AG, 4070 Basel, Switzerland;
Jean-Philippe
JP
Carralot
Office of Innovation, Hoffman-La Roche AG, 4070 Basel, Switzerland;
Marco
M
Prunotto
Roche Pharmaceutical Research & Early Development, Discovery Oncology, Innovation Center Penzberg, Roche Diagnostics GmbH, 82377 Penzberg, Germany.
Gerhard
G
Niederfellner
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; pastani@mail.nih.gov.
Ira
I
Pastan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003609:Dactinomycin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D000922:Immunotoxins / Q000008:administration & dosage*; D000090204:Mesothelin; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D018796:Immunoconjugates; D000922:Immunotoxins; C000715528:Msln protein, mouse; D016328:NF-kappa B; D003609:Dactinomycin; C000597116:LMB-100; D000090204:Mesothelin
apoptosis; cancer therapy; immunotherapy; mesothelioma; pancreatic cancer