TY - JOUR
T1 - Identification of Compounds That Decrease Glioblastoma Growth and Glucose Uptake in Vitro
AU - Libby, Catherine J.
AU - Zhang, Sixue
AU - Benavides, Gloria A.
AU - Scott, Sarah E.
AU - Li, Yanjie
AU - Redmann, Matthew
AU - Tran, Anh Nhat
AU - Otamias, Arphaxad
AU - Darley-Usmar, Victor
AU - Napierala, Marek
AU - Zhang, Jianhua
AU - Augelli-Szafran, Corinne Elizabeth
AU - Zhang, Wei
AU - Hjelmeland, Anita B.
N1 - Funding Information:
*Phone: 205-996-4596. E-mail: hjelmea@uab.edu. *E-mail: zhangwee@yahoo.com. ORCID Corinne Elizabeth Augelli-Szafran: 0000-0002-7676-6120 Anita B. Hjelmeland: 0000-0003-2200-3248 Funding This work was supported by National Institutes of Health grant R21NS096531 to A.B.H., T32NS048039 to C.J.L., and in part by P30 G050886-01 to J.Z. and R01NS081366 to M.N., the UAB mitochondrial medicine laboratory and startup funds from the University of Alabama at Birmingham. These startup funds include contributions from the Department of Cell, Developmental and Integrative Biology, the Comprehensive Cancer Center, the Civitan International Research Center for Glial Biology in Medicine, the Center for Free Radical Biology, and the Neuro-Oncology Brain SPORE Notes The authors declare no competing financial interest.
Funding Information:
This work was supported by National Institutes of Health grant R21NS096531 to A.B.H. T32NS048039 to C.J.L., and in part by P30 G050886-01 to J.Z. and R01NS081366 to M.N., the UAB mitochondrial medicine laboratory and startup funds from the University of Alabama at Birmingham. These startup funds include contributions from the Department of Cell, Developmental and Integrative Biology, the Comprehensive Cancer Center, the Civitan International Research Center for Glial Biology in Medicine, the Center for Free Radical Biology, and the Neuro-Oncology Brain SPORE
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/8/17
Y1 - 2018/8/17
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85051716282&partnerID=8YFLogxK
U2 - 10.1021/acschembio.8b00251
DO - 10.1021/acschembio.8b00251
M3 - Article
C2 - 29905460
AN - SCOPUS:85051716282
SN - 1554-8929
VL - 13
SP - 2048
EP - 2057
JO - ACS chemical biology
JF - ACS chemical biology
IS - 8
ER -