KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice

ES Polson, VB Kuchler, C Abbosh, EM Ross, RK Mathew, HA Beard, B da Silva, AN Holding, S Ballereau, E Chuntharpursat-Bon, J Williams, HBS Griffiths, H Shao, A Patel, AJ Davies, A Droop, P Chumas, SC Short, M Lorger, JE GestwickiLD Roberts, RS Bon, SJ Allison, S Zhu, F Markowetz, H Wurdak

Research output: Contribution to journalArticlepeer-review

Abstract

Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM.
Original languageEnglish
Article numbereaar2718
Number of pages13
JournalScience Translational Medicine
Volume10
Issue number454
DOIs
Publication statusPublished - 15 Aug 2018

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