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.
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Acknowledgments
Financial support for this research was provided by Nemours Research Programs, National Institutes of Health Grant 8P20GM103464, National Institutes of Health Grant P20RR016472 and Alex’s Lemonade Stand Foundation. We wish to thank Matthew R. England for initial assistance in proteomic studies, Dr. M. David Percival (Merck Frosst Centre for Therapeutic Research, Quebec, Canada) for generously providing the L-006235, L-625, and L-264 cathepsin inhibitory compounds and Dr. James McKerrow (University of California, San Francisco) for kindly providing cathepsin inhibitory agent K11777 and the rest of our colleagues for helpful discussions.
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Authors have no financial or personal relationships with other people or organizations that could inappropriately influence this work.
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Cartledge, D.M., Colella, R., Glazewski, L. et al. Inhibitors of cathepsins B and L induce autophagy and cell death in neuroblastoma cells. Invest New Drugs 31, 20–29 (2013). https://doi.org/10.1007/s10637-012-9826-6
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DOI: https://doi.org/10.1007/s10637-012-9826-6