Targeting the Akt-pathway to Improve Radiosensitivity in Glioblastoma

Narayan, Ravi S.; Fedrigo, Carlos Alexandre; Stalpers, Lukas J.A.; Baumert, Brigitta G.; Sminia, Peter

doi:10.2174/13816128130513

Cited by 3 publications

(3 citation statements)

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“…There is substantial experimental evidence to demonstrate that increased radiation resistance is associated with pro-survival pathways including PI3K-AKT [25][26][27][28][29] and TORC1/TORC2 [29,30]. Here, we show that P529, a TORC1/TORC2 inhibitor, effectively blocks downstream targets and results in radiosensitization in preclinical Pca models.…”

Section: Discussionmentioning

confidence: 76%

Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1‐mediated survivin function and delaying DNA repair in prostate cancer models

et al. 2014

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Section: Discussionmentioning

confidence: 76%

Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1‐mediated survivin function and delaying DNA repair in prostate cancer models

et al. 2014

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“…Experimental data has indicated that phosphorylated AKT is required for proper DNA-damage response (DDR) during Non-Homologous end-joining (NHEJ) by binding to DNA-PKcs and promoting its auto-phosphorylation [ 9 , 10 ]. Pharmacological inhibition of AKT has therefore also been found to sensitize cancer cells to DNA damaging agents and radiotherapy [ 11 , 12 ]. In recent years many specific PI3K/AKT/mTOR pathway targeted agents have become available for preclinical studies and clinical evaluation [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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BackgroundGlioblastoma 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.MethodsThe 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.ResultsA 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).ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3193-9) contains supplementary material, which is available to authorized users.

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“…Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a frequent occurrence in GBM. Activation of the PI3K-Akt pathway results in disturbance of control of cell growth and cell survival, which contributes to a competitive growth advantage, metastatic competence as well as to therapy resistance [ 24 ]. Moreover, irradiation induces Akt activation in GBM cells and increases radioresistance, thus Akt may be a central player in a feedback loop [ 25 ].…”

Section: Phosphatidylinositol 3-kinase (Pi3k)/ Akt Pathwaymentioning

confidence: 99%