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Published on: June 20, 2015
The FDA-Approved Anthelmintic Pyrvinium Pamoate Inhibits Pancreatic Cancer Cells in Nutrient-Depleted Conditions by
Christopher W Schultz1, Grace A McCarthy2, Teena Nerwal1
1The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
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).
Insights
Pyrvinium pamoate effectively targets pancreatic cancer by inhibiting mitochondrial pathways and RNA transcription. This FDA-approved drug shows promise in treating pancreatic ductal adenocarcinoma, even in low-glucose conditions.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer exacerbated by its microenvironment, leading to metabolic alterations.
- The FDA-approved drug pyrvinium pamoate (PP) has shown potential against PDAC, but its mechanism of action requires elucidation.
Purpose of the Study:
- To investigate the mechanism by which pyrvinium pamoate inhibits pancreatic ductal adenocarcinoma cell viability and tumor growth.
- To determine the efficacy of pyrvinium pamoate in preclinical models of pancreatic cancer, including its effectiveness under hypoglycemic conditions.
Main Methods:
- Assessed PDAC cell viability using nanomolar IC50 values across various cell lines and organoids.
- Evaluated tumor growth inhibition in PDAC xenografts following intraperitoneal and oral administration of pyrvinium pamoate.
- Utilized metabolomic, phosphoproteomic, and RNA sequencing analyses to identify PP's molecular targets and pathways.
Main Results:
- Pyrvinium pamoate demonstrated potent inhibition of PDAC cell viability (IC50: 9-93 nmol/L) and xenograft tumor growth.
- PP treatment significantly inhibited mitochondrial oxidative phosphorylation and fatty acid metabolism, leading to increased glycolysis.
- PP selectively bound mitochondrial G-quadruplexes, inhibiting mitochondrial RNA transcription and reducing mitochondrial-encoded gene expression by 90%.
Conclusions:
- Pyrvinium pamoate effectively targets pancreatic ductal adenocarcinoma by disrupting mitochondrial function and transcription.
- The drug's enhanced efficacy in hypoglycemic conditions mirrors the tumor microenvironment, suggesting therapeutic potential.
- A clinical trial is planned to further evaluate pyrvinium pamoate's efficacy in PDAC patients.
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