The FDA-approved anthelmintic pyrvinium pamoate inhibits pancreatic cancer cells in nutrient-depleted conditions by targeting the mitochondria

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. PishvaianTalia Golan, Charles J. Yeo, Emanuel F. Petricoin, George C. Prendergast, Joseph Salvino, Pankaj K. Singh, Dan A. Dixon, Jonathan R. Brody

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 ¼ 0.0023) of human-grade drug. Meta-bolomic 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).

Original languageEnglish (US)
Pages (from-to)2166-2176
Number of pages11
JournalMolecular cancer therapeutics
Volume20
Issue number11
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'The FDA-approved anthelmintic pyrvinium pamoate inhibits pancreatic cancer cells in nutrient-depleted conditions by targeting the mitochondria'. Together they form a unique fingerprint.

Cite this