Identification of Compounds That Decrease Glioblastoma Growth and Glucose Uptake in Vitro

Catherine J. Libby, Sixue Zhang, Gloria A. Benavides, Sarah E. Scott, Yanjie Li, Matthew Redmann, Anh Nhat Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Corinne Elizabeth Augelli-Szafran, Wei Zhang, Anita B. Hjelmeland

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Tumor heterogeneity has hampered the development of novel effective therapeutic options for aggressive cancers, including the deadly primary adult brain tumor glioblastoma (GBM). Intratumoral heterogeneity is partially attributed to the tumor initiating cell (TIC) subset that contains highly tumorigenic, stem-like cells. TICs display metabolic plasticity but can have a reliance on aerobic glycolysis. Elevated expression of GLUT1 and GLUT3 is present in many cancer types, with GLUT3 being preferentially expressed in brain TICs (BTICs) to increase survival in low nutrient tumor microenvironments, leading to tumor maintenance. Through structure-based virtual screening (SBVS), we identified potential novel GLUT inhibitors. The screening of 13 compounds identified two that preferentially inhibit the growth of GBM cells with minimal toxicity to non-neoplastic astrocytes and neurons. These compounds, SRI-37683 and SRI-37684, also inhibit glucose uptake and decrease the glycolytic capacity and glycolytic reserve capacity of GBM patient-derived xenograft (PDX) cells in glycolytic stress test assays. Our results suggest a potential new therapeutic avenue to target metabolic reprogramming for the treatment of GBM, as well as other tumor types, and the identified novel inhibitors provide an excellent starting point for further lead development.

Original languageEnglish (US)
Pages (from-to)2048-2057
Number of pages10
JournalACS chemical biology
Volume13
Issue number8
DOIs
StatePublished - Aug 17 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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