TY  - JOUR
A1  - Heinzen, Dennis
A1  - Divé, Iris
A1  - Lorenz, Nadja Irene
A1  - Luger, Anna-Luisa
A1  - Steinbach, Joachim Peter
A1  - Ronellenfitsch, Michael Wilfried
T1  - Second generation mtor inhibitors as a double-edged sword in malignant glioma treatment
T2  - International journal of molecular sciences
N2  - Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.
KW  - glioblastoma
KW  - mTOR
KW  - mTOR inhibition
KW  - hypoxia
KW  - starvation
KW  - tumor microenvironment
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/52540
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-525405
SN  - 1422-0067
SN  - 1661-6596
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 20
IS  - 18, Art. 4474
SP  - 1
EP  - 13
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -