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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Cancer 1/2017

The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

Zeitschrift:
BMC Cancer > Ausgabe 1/2017
Autoren:
Ravi S. Narayan, Carlos A. Fedrigo, Eelke Brands, Rogier Dik, Lukas J.A. Stalpers, Brigitta G. Baumert, Ben J. Slotman, Bart A. Westerman, Godefridus J. Peters, Peter Sminia
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12885-017-3193-9) contains supplementary material, which is available to authorized users.

Abstract

Background

Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro.

Methods

The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, −migration and on expression of key proteins in the PI3K-AKT pathway by western blot.

Results

A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM).

Conclusions

The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.
Zusatzmaterial
Additional file 1: Figure S1. A) Number of cells invaded through matrigel after 16 h in the presence of 4 Gy combined with 1 μM (Left) or 10 μM (Right) MK2206. Error bars represent SD over 3 replicates, * = p < 0.05. B) U87 cells untreated. Migration of U87 cells into wound up to 8 h (Left). Migration of U87 cells out of attached spheroids up to 4 days after spheroid plating (Right). (PDF 356 kb)
12885_2017_3193_MOESM1_ESM.pdf
Literatur
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