Treatment with cyclic amp activators reduces glioblastoma growth and invasion as assessed by two‐photon microscopy

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 ef-fect—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, 1mM) 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 for-skolin treatment (F2,249 = 5.968, p = 0.0029). 3D volumetric quantification utilizing two‐photon fluo-rescence microscopy revealed that the treated tumors maintained a spheric shape while the un-treated controls exhibited the GB typical invasive growth pattern. (4) Conclusions: Our data demon-strate that treatment with a cAMP analog/activator reduces GB growth and invasion.