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Open AccessArticle
Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment
by
Ayenachew Bezawork-Geleta
Ayenachew Bezawork-Geleta 1,*,
Diane Moujalled
Diane Moujalled 2,3,
David P. De Souza
David P. De Souza 4,
Vinod K. Narayana
Vinod K. Narayana 4,
James Dimou
James Dimou 5,6,
Rodney Luwor
Rodney Luwor 5,7,8,9 and
Matthew J. Watt
Matthew J. Watt 1
1
Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
2
Blood Cells & Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
3
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
4
Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
5
Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia
6
Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia
7
Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
8
Federation University, Ballarat, VIC 3350, Australia
9
Huagene Institute, Kecheng Science and Technology Park, Pukou District, Nanjing 211806, China
*
Author to whom correspondence should be addressed.
Metabolites 2024, 14(8), 413; https://doi.org/10.3390/metabo14080413 (registering DOI)
Submission received: 1 July 2024
/
Revised: 17 July 2024
/
Accepted: 23 July 2024
/
Published: 27 July 2024
Abstract
Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood–brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches.
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MDPI and ACS Style
Bezawork-Geleta, A.; Moujalled, D.; Souza, D.P.D.; Narayana, V.K.; Dimou, J.; Luwor, R.; Watt, M.J.
Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment. Metabolites 2024, 14, 413.
https://doi.org/10.3390/metabo14080413
AMA Style
Bezawork-Geleta A, Moujalled D, Souza DPD, Narayana VK, Dimou J, Luwor R, Watt MJ.
Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment. Metabolites. 2024; 14(8):413.
https://doi.org/10.3390/metabo14080413
Chicago/Turabian Style
Bezawork-Geleta, Ayenachew, Diane Moujalled, David P. De Souza, Vinod K. Narayana, James Dimou, Rodney Luwor, and Matthew J. Watt.
2024. "Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment" Metabolites 14, no. 8: 413.
https://doi.org/10.3390/metabo14080413
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