Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death.
Therapies that target the signal transduction and metabolic pathways of cancer stem cells (CSCs) are innovative strategies to effectively reduce the recurrence and significantly improve the outcome of glioblastoma multiforme (GBM). CSCs exhibit an increased rate of glycolysis, thus rendering them intrinsically more sensitive to prospective therapeutic strategies based on the inhibition of the glycolytic pathway. The enzyme lactate dehydrogenase-A (LDH-A), which catalyses the interconversion of pyruvate and lactate, is up-regulated in human cancers, including GBM. Although several papers have explored the benefits of targeting cancer metabolism in GBM, the effects of direct LDH-A inhibition in glial tumours have not yet been investigated, particularly in the stem cell subpopulation. Here, two representative LDH-A inhibitors (NHI-1 and NHI-2) were studied in GBM-derived CSCs and compared to differentiated tumour cells. LDH-A inhibition was particularly effective in CSCs isolated from different GBM cell lines, where the two compounds blocked CSC formation and elicited long-lasting effects by triggering both apoptosis and cellular differentiation. These data demonstrate that GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition and shed light on the therapeutic potential of LDH-A inhibitors in this tumour type.
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Simona
S
Daniele
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Chiara
C
Giacomelli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Elisa
E
Zappelli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Carlotta
C
Granchi
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Maria Letizia
ML
Trincavelli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Filippo
F
Minutolo
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Claudia
C
Martini
D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D053078:Membrane Potential, Mitochondrial
D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5