Pyrvinium targets autophagy addiction to promote cancer cell death.

Abstract

Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity. Here we demonstrate that pyrvinium inhibits autophagy both in vitro and in vivo. We further demonstrate that the inhibition of autophagy is mammalian target of rapamycin independent but depends on the transcriptional inhibition of autophagy genes. Moreover, the combination of pyrvinium with autophagy stimuli improves its toxicity against cancer cells, and pretreatment of cells with 3-MA or siBeclin1 partially protects cells from pyrvinium-induced cell death under glucose starvation, suggesting that targeted autophagy addiction is involved in pyrvinium-mediated cytotoxicity. Finally, in vivo studies show that the combination therapy of pyrvinium with the anticancer and autophagy stimulus agent, 2-deoxy-D-glucose (2-DG), is significantly more effective in inhibiting tumor growth than pyrvinium or 2-DG alone. This study supports a novel cancer therapeutic strategy based on targeting autophagy addiction and implicates using pyrvinium as an autophagy inhibitor in combination with chemotherapeutic agents to improve their therapeutic efficacy.

• Authors: Longfei Deng, Yunlong Lei, Rui Liu, Jingyi Li, Kefei Yuan, Yi Li, Yi Chen, Yi Liu, You Lu, Carl K Edwards 3rd, Canhua Huang, Yuquan Wei
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e614 (May 02 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 23640456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• Pyrvinium Compounds
• pyrvinium
• Deoxyglucose
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Autophagy (drug effects)
• Cell Line
• Deoxyglucose (pharmacology, therapeutic use)
• Female
• HCT116 Cells
• HEK293 Cells
• HeLa Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Microtubule-Associated Proteins (metabolism)
• Neoplasms (drug therapy)
• Pyrvinium Compounds (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (metabolism)
• Transplantation, Heterologous
• Zebrafish