PRECLINICAL STUDIES

Investigational New Drugs

, Volume 31, Issue 1, pp 20-29

First online:

Inhibitors of cathepsins B and L induce autophagy and cell death in neuroblastoma cells

  • Donna M. CartledgeAffiliated withNemours Biomedical Research, Alfred I. duPont Hospital for Children
  • , Rita ColellaAffiliated withNemours Biomedical Research, Alfred I. duPont Hospital for ChildrenDepartment of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine
  • , Lisa GlazewskiAffiliated withNemours Biomedical Research, Alfred I. duPont Hospital for Children
  • , Guizhen LuAffiliated withNemours Biomedical Research, Alfred I. duPont Hospital for Children
  • , Robert W. MasonAffiliated withNemours Biomedical Research, Alfred I. duPont Hospital for Children Email author 

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Summary

This study was designed to test the hypothesis that specific inhibition of cathepsins B and L will cause death of neuroblastoma cells. Five compounds that differ in mode and rate of inhibition of these two enzymes were all shown to cause neuroblastoma cell death. Efficacy of the different compounds was related to their ability to inhibit the activity of the isolated enzymes. A dose- and time-response for induction of cell death was demonstrated for each compound. A proteomic study showed that inhibitor treatment caused an increase of markers of cell stress, including induction of levels of the autophagy marker, LC-3-II. Levels of this marker protein were highest at cytotoxic inhibitor concentrations, implicating autophagy in the cell death process. An in vivo mouse model showed that one of these inhibitors markedly impaired tumor growth. It is concluded that development of drugs to target these two proteases may provide a novel approach to treating neuroblastoma.

Keywords

Neuroblastoma Cathepsin Inhibitor Autophagy