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

Euan S Polson, Verena B Kuchler, Christopher Abbosh, Edith M Ross, Ryan K Mathew, Hester A Beard, Bárbara da Silva, Andrew N Holding, Stephane Ballereau, Eulashini Chuntharpursat-Bon, Jennifer Williams, Hollie B S Griffiths, Hao Shao, Anjana Patel, Adam J Davies, Alastair Droop, Paul Chumas, Susan C Short, Mihaela Lorger, Jason E Gestwicki & 6 others Lee D Roberts, Robin S Bon, Simon J Allison, Shoutian Zhu, Florian Markowetz, Heiko Wurdak

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 number2718
JournalScience Translational Medicine
Volume10
Issue number454
DOIs
Publication statusPublished - 15 Aug 2018

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Glioblastoma
Energy Metabolism
Growth
Neoplasms
Heat-Shock Proteins
Mitochondrial Proteins
Metabolic Networks and Pathways
Heterografts
Brain Neoplasms
Cell Death
KHS101
Pharmacology
Cell Line
Survival
Brain

Cite this

Polson, E. S., Kuchler, V. B., Abbosh, C., Ross, E. M., Mathew, R. K., Beard, H. A., ... Wurdak, H. (2018). KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice. Science Translational Medicine, 10(454), [2718]. https://doi.org/10.1126/scitranslmed.aar2718
Polson, Euan S ; Kuchler, Verena B ; Abbosh, Christopher ; Ross, Edith M ; Mathew, Ryan K ; Beard, Hester A ; da Silva, Bárbara ; Holding, Andrew N ; Ballereau, Stephane ; Chuntharpursat-Bon, Eulashini ; Williams, Jennifer ; Griffiths, Hollie B S ; Shao, Hao ; Patel, Anjana ; Davies, Adam J ; Droop, Alastair ; Chumas, Paul ; Short, Susan C ; Lorger, Mihaela ; Gestwicki, Jason E ; Roberts, Lee D ; Bon, Robin S ; Allison, Simon J ; Zhu, Shoutian ; Markowetz, Florian ; Wurdak, Heiko. / KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice. In: Science Translational Medicine. 2018 ; Vol. 10, No. 454.
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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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Polson, ES, Kuchler, VB, Abbosh, C, Ross, EM, Mathew, RK, Beard, HA, da Silva, B, Holding, AN, Ballereau, S, Chuntharpursat-Bon, E, Williams, J, Griffiths, HBS, Shao, H, Patel, A, Davies, AJ, Droop, A, Chumas, P, Short, SC, Lorger, M, Gestwicki, JE, Roberts, LD, Bon, RS, Allison, SJ, Zhu, S, Markowetz, F & Wurdak, H 2018, 'KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice', Science Translational Medicine, vol. 10, no. 454, 2718. https://doi.org/10.1126/scitranslmed.aar2718

KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice. / Polson, Euan S; Kuchler, Verena B; Abbosh, Christopher; Ross, Edith M; Mathew, Ryan K; Beard, Hester A; da Silva, Bárbara; Holding, Andrew N; Ballereau, Stephane; Chuntharpursat-Bon, Eulashini; Williams, Jennifer; Griffiths, Hollie B S; Shao, Hao; Patel, Anjana; Davies, Adam J; Droop, Alastair; Chumas, Paul; Short, Susan C; Lorger, Mihaela; Gestwicki, Jason E; Roberts, Lee D; Bon, Robin S; Allison, Simon J; Zhu, Shoutian; Markowetz, Florian; Wurdak, Heiko.

In: Science Translational Medicine, Vol. 10, No. 454, 2718, 15.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice

AU - Polson, Euan S

AU - Kuchler, Verena B

AU - Abbosh, Christopher

AU - Ross, Edith M

AU - Mathew, Ryan K

AU - Beard, Hester A

AU - da Silva, Bárbara

AU - Holding, Andrew N

AU - Ballereau, Stephane

AU - Chuntharpursat-Bon, Eulashini

AU - Williams, Jennifer

AU - Griffiths, Hollie B S

AU - Shao, Hao

AU - Patel, Anjana

AU - Davies, Adam J

AU - Droop, Alastair

AU - Chumas, Paul

AU - Short, Susan C

AU - Lorger, Mihaela

AU - Gestwicki, Jason E

AU - Roberts, Lee D

AU - Bon, Robin S

AU - Allison, Simon J

AU - Zhu, Shoutian

AU - Markowetz, Florian

AU - Wurdak, Heiko

N1 - Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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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U2 - 10.1126/scitranslmed.aar2718

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