The FDA-Approved Anthelmintic Pyrvinium Pamoate Inhibits Pancreatic Cancer Cells in Nutrient-Depleted Conditions by Targeting the Mitochondria
Year: 2021
Type: article
Abstract: 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).
Source: Molecular Cancer Therapeutics
Authors: Christopher W. Schultz, Grace A. McCarthy, Teena Nerwal, Avinoam Nevler, James B. DuHadaway, Matthew D. McCoy, Wei Jiang, Samantha Z. Brown, Austin Goetz, Aditi Jain, Valerie S. Calvert, Vikalp Vishwakarma, Dezhen Wang, Ranjan Preet, Joel Cassel, Ross Summer, Hoora Shaghaghi, Yves Pommier, Simone A. Baechler, Michael J. Pishvaian, Talia Golan, Charles J. Yeo, Emanuel F. Petricoin, George C. Prendergast, Joseph Salvino, Pankaj K. Singh, Dan A. Dixon, Jonathan R. Brody
Institutions: Thomas Jefferson University, Thomas Jefferson University Hospital, Oregon Health & Science University, Lankenau Institute for Medical Research, Georgetown University, George Mason University, University of Kansas, University of Nebraska Medical Center, The Wistar Institute, National Cancer Institute, Johns Hopkins University, Tel Aviv University, Sheba Medical Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1581679921, G1797368095, G246298631, G2766465774, G2822956262, G3469626005, G3607157868, G4021451954, G4447571086, Pancreatic Cancer Metastasis, G7793961685, G9000073711, G9000173957, Translational Research in Cancer, Consolidated Basic Cancer Research Program, OHSU Knight Cancer Institute, G911360726
OpenAlex ID: W3194569608