Pyrvinium targets autophagy addiction to promote cancer cell death

Longfei Deng,Canhua Huang,Yi Chen,Rui Liu,Yunlong Lei,Yi Li,Kefei Yuan,Yi Liu,Jingyi Li,You Lu,Carl K Edwards Iii,Yuquan Wei

doi:10.1038/cddis.2013.142

Longfei Deng, Canhua Huang + Show 10 more

Open Access

https://doi.org/10.1038/cddis.2013.142

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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.

Highlights

In normal physiological conditions, autophagy proceeds at a modest basal level in virtually all cells to carry out homeostatic functions such as protein and organelle turnover
We found that the inhibiton of autophagy by pyrvinium was dose-dependent with an IC50 of 50 nM (Figure 1d)
Using zebrafish and mice to assess the effects of pyrvinium on autophagy in vivo, we found that pyrvinium decreases their autophagy levels

Summary

Introduction

Autophagy proceeds at a modest basal level in virtually all cells to carry out homeostatic functions such as protein and organelle turnover. In response to such diverse stimuli as starvation, genotoxic chemicals and pathogen infection, autophagy process is induced for the maintenance of cellular metabolism or for the clearance of aggregated proteins, damaged organelles and intracellular pathogens, facilitating cell survival.[5] Likewise, many anticancer agents are stressors requiring the autophagy response that assists the cancer cells to survive the crisis, and such cancer cells are in a state of ‘autophagy addiction’.6. We demonstrate that pyrvinium potently inhibits autophagy by suppressing the transcription of autophagy genes and that targeting autophagy addiction by pyrvinium shows effective anticancer activity both in vitro and in vivo

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