2. Academic Validation
  3. KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice

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

  • Sci Transl Med. 2018 Aug 15;10(454):eaar2718. doi: 10.1126/scitranslmed.aar2718.
Euan S Polson 1,  Verena B Kuchler 1,  Christopher Abbosh 1,  Edith M Ross 2,  Ryan K Mathew 1 3,  Hester A Beard 4,  Bárbara da Silva 1,  Andrew N Holding 2,  Stephane Ballereau 2,  Eulashini Chuntharpursat-Bon 1,  Jennifer Williams 1,  Hollie B S Griffiths 5,  Hao Shao 6,  Anjana Patel 1,  Adam J Davies 1,  Alastair Droop 1,  Paul Chumas 3,  Susan C Short 1,  Mihaela Lorger 1,  Jason E Gestwicki 6,  Lee D Roberts 1,  Robin S Bon 1 4,  Simon J Allison 5,  Shoutian Zhu 7,  Florian Markowetz 2,  Heiko Wurdak 8
Affiliations

Affiliations

  • 1 School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
  • 2 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
  • 3 Department of Neurosurgery, Leeds General Infirmary, Leeds LS1 3EX, UK.
  • 4 School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
  • 5 School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
  • 6 Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA.
  • 7 California Institute for Biomedical Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA.
  • 8 School of Medicine, University of Leeds, Leeds LS2 9JT, UK. h.wurdak@leeds.ac.uk.
PMID: 30111643 DOI: 10.1126/scitranslmed.aar2718
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.

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