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Treatment with Cyclic AMP Activators Reduces Glioblastoma Growth and Invasion as Assessed by Two-Photon Microscopy
Krista Minéia Wartchow1,2, Benjamin Schmid3, Philipp Tripal3
1Department of Neurosurgery, Friedrich-Alexander University, 91054 Erlangen, Germany.
Abstract:
(1) Background: Despite progress in surgery and radio-chemotherapy of glioblastoma (GB), the prognosis remains very poor. GB cells exhibit a preference for hypoxia to maintain their tumor-forming capacity. Enhancing oxidative phosphorylation-known as the anti-Warburg effect-with cyclic AMP activators has been demonstrated to drive GB cells from proliferation to differentiation thereby reducing tumor growth in a cell culture approach. Here we re-evaluate this treatment in a more clinically relevant model. (2) Methods: The effect of treatment with dibutyryl cyclic AMP (dbcAMP, 1 mM) and the cAMP activator forskolin (50µM) was assessed in a GB cell line (U87GFP+, 104 cells) co-cultured with mouse organotypic brain slices providing architecture and biochemical properties of normal brain tissue. Cell viability was determined by propidium-iodide, and gross metabolic effects were excluded in the extracellular medium. Tumor growth was quantified in terms of area, volume, and invasion at the start of culture, 48 h, 7 days, and 14 days after treatment. (3) Results: The tumor area was significantly reduced following dbcAMP or forskolin treatment (F2,249 = 5.968, p = 0.0029). 3D volumetric quantification utilizing two-photon fluorescence microscopy revealed that the treated tumors maintained a spheric shape while the untreated controls exhibited the GB typical invasive growth pattern. (4) Conclusions: Our data demonstrate that treatment with a cAMP analog/activator reduces GB growth and invasion.
Insights
Cyclic AMP activators significantly reduced glioblastoma (GB) growth and invasion in a brain slice model. This approach shifts GB cells from proliferation to differentiation, offering a potential new therapeutic strategy for this aggressive brain tumor.
Area of Science:
- Neuro-oncology
- Cancer biology
- Molecular medicine
Background:
- Glioblastoma (GB) remains a challenging brain tumor with poor prognosis despite current treatments.
- GB cells thrive in hypoxic conditions, utilizing the Warburg effect for proliferation.
- Targeting metabolic pathways, like enhancing oxidative phosphorylation via cyclic AMP (cAMP) activators, shows promise in reducing GB growth.
Purpose of the Study:
- To investigate the efficacy of cAMP activators in reducing glioblastoma growth and invasion using a more clinically relevant organotypic brain slice model.
- To re-evaluate the anti-Warburg effect strategy in a complex tissue environment.
Main Methods:
- A glioblastoma cell line (U87GFP+) was co-cultured with mouse organotypic brain slices.
- Cells were treated with dibutyryl cyclic AMP (dbcAMP) or forskolin, cAMP activators.
- Tumor growth (area, volume) and invasion were quantified using microscopy over 14 days.
Main Results:
- Treatment with dbcAMP or forskolin significantly reduced glioblastoma tumor area.
- 3D volumetric analysis showed treated tumors maintained a spherical shape, unlike untreated controls which exhibited invasive growth.
- Cell viability assays confirmed treatment effects, excluding gross metabolic alterations.
Conclusions:
- cAMP analogs and activators effectively reduce glioblastoma growth and invasion in an organotypic brain slice model.
- This suggests a potential therapeutic strategy for glioblastoma by promoting cell differentiation over proliferation.
- The findings support targeting the anti-Warburg effect in glioblastoma treatment.
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