The FDA-Approved Anthelmintic Pyrvinium Pamoate Inhibits Pancreatic Cancer Cells in Nutrient-Depleted Conditions by Targeting the Mitochondria
| Autor: | Dan A. Dixon, Talia Golan, James B. DuHadaway, Teena Nerwal, Austin Goetz, Simone A Baechler, Yves Pommier, Avinoam Nevler, Michael J. Pishvaian, Emanuel F. Petricoin, Charles J. Yeo, Valerie S. Calvert, Pankaj K. Singh, Christopher W. Schultz, Joel Cassel, Wei Jiang, Dezhen Wang, Vikalp Vishwakarma, Aditi Jain, Matthew McCoy, Grace A. McCarthy, Joseph M. Salvino, Ranjan Preet, George C. Prendergast, Samantha Z Brown, Ross Summer, Hoorah Shaghaghi, Jonathan R. Brody |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Programmed cell death endocrine system diseases Mitochondrion Adenocarcinoma Article Mice Pyrvinium Compounds In vivo Pancreatic cancer medicine Organoid Animals Humans Metabolomics Viability assay Anthelmintics Chemistry United States Food and Drug Administration Hypoxia (medical) medicine.disease Survival Analysis digestive system diseases United States Oncology Cell culture Cancer research medicine.symptom Carcinoma Pancreatic Ductal |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is a lethal aggressive cancer, in part due to elements of the microenvironment (hypoxia, hypoglycemia) that cause metabolic network alterations. The FDA-approved antihelminthic pyrvinium pamoate (PP) has previously been shown to cause PDAC cell death, although the mechanism has not been fully determined. We demonstrated that PP effectively inhibited PDAC cell viability with nanomolar IC50 values (9–93 nmol/L) against a panel of PDAC, patient-derived, and murine organoid cell lines. In vivo, we demonstrated that PP inhibited PDAC xenograft tumor growth with both intraperitoneal (IP; P < 0.0001) and oral administration (PO; P = 0.0023) of human-grade drug. Metabolomic and phosphoproteomic data identified that PP potently inhibited PDAC mitochondrial pathways including oxidative phosphorylation and fatty acid metabolism. As PP treatment reduced oxidative phosphorylation (P < 0.001), leading to an increase in glycolysis (P < 0.001), PP was 16.2-fold more effective in hypoglycemic conditions similar to those seen in PDAC tumors. RNA sequencing demonstrated that PP caused a decrease in mitochondrial RNA expression, an effect that was not observed with established mitochondrial inhibitors rotenone and oligomycin. Mechanistically, we determined that PP selectively bound mitochondrial G-quadruplexes and inhibited mitochondrial RNA transcription in a G-quadruplex–dependent manner. This subsequently led to a 90% reduction in mitochondrial encoded gene expression. We are preparing to evaluate the efficacy of PP in PDAC in an IRB-approved window-of-opportunity trial (IND:144822). |
| Databáze: | OpenAIRE |
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