Abstract
BackgroundGlioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (GlaB) has been recently identified as the first direct inhibitor of Gli1, the downstream effector of the pathway.MethodsWe established the overexpression of Gli1 in murine glioma cells (GL261) and GlaB effect on cell viability. We used 1H-nuclear magnetic resonance (NMR) metabolomic approach to obtain informative metabolic snapshots of GL261 cells acquired at different time points during GlaB treatment. The activation of AMP activated protein Kinase (AMPK) induced by GlaB was established by western blot. After the orthotopic GL261 cells injection in the right striatum of C57BL6 mice and the intranasal (IN) GlaB/mPEG5kDa-Cholane treatment, the tumor growth was evaluated. The High Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS) was used to quantify GlaB in brain extracts of treated mice.ResultsWe found that GlaB affected the growth of murine glioma cells both in vitro and in vivo animal model. Using an untargeted 1H-NMR metabolomic approach, we found that GlaB stimulated the glycolytic metabolism in glioma, increasing lactate production. The high glycolytic rate could in part support the cytotoxic effects of GlaB, since the simultaneous blockade of lactate efflux with α-cyano-4-hydroxycinnamic acid (ACCA) affected glioma cell growth. According to the metabolomic data, we found that GlaB increased the phosphorylation of AMPK, a cellular energy sensor involved in the anabolic-to-catabolic transition.ConclusionsOur results indicate that GlaB inhibits glioma cell growth and exacerbates Warburg effect, increasing lactate production. In addition, the simultaneous blockade of Gli1 and lactate efflux amplifies the anti-tumor effect in vivo, providing new potential therapeutic strategy for this brain tumor.Graphical
Highlights
Glioma is the most common and primary brain tumors in adults
We found that Glabrescione B (GlaB) treatment of Murine glioma cells (GL261) glioma cells inhibits Gli1 transcription, reducing glioma cell growth
In order to investigate the role of Gli1 in GL261 proliferation, we evaluated the effect of GlaB treatment (5 μM) on cell viability
Summary
Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The role of Hh in the infiltrative growth of glioma remains to be elucidated, several studies claim its involvement in the promotion of cell proliferation, cancer stem cell self-renewal and tumor progression [15,16,17]. This pathway already emerged as a therapeutic target in oncology [18,19,20] and we have recently identified the first natural small molecule able to interfere with Gli activity [19], Glabrescione B (GlaB). GlaB binds to Gli, and impairs its activity interfering with DNA interaction [19]
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