Priyanka Gupta1, Kumaravelu Jagavelu2, Durga Prasad Mishra1. 1. 1 Endocrinology Division, Cell Death Research Laboratory, CSIR-Central Drug Research Institute , Lucknow, India . 2. 2 Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India .
Abstract
AIMS: 2-Deoxy-d-glucose (2-DG), a synthetic glycolytic inhibitor, is currently under clinical evaluation as a promising anticancer agent. However, 2-DG treatment in cancer cells activates prosurvival Akt signaling that might limit its clinical efficacy. The NADPH oxidase 4 (Nox-4)/reactive oxygen species/Akt signaling is known to regulate survival, proliferation, infiltration, and invasion in glioblastomas (GBMs). The enhanced motility, invasiveness, and therapy resistance in GBMs are attributed to metabolic adaptation through increased aerobic glycolysis. Therefore, we hypothesized that inhibition of the Nox-4 might enhance 2-DG-induced suppression of glycolysis, migration, and invasion in GBM cells. RESULTS: We identified the natural naphthoquinone compound shikonin as a potent inhibitor of the Nox-4/Akt signaling pathway. The combined treatment of shikonin+2-DG suppressed the glycolytic phenotype, migration, and invasion through modulation of the Akt/HIF1α/hexokinase-2 signaling axis in GBM cells. The combination also exhibited enhanced antiproliferative and antiangiogenic effects in vivo. INNOVATION: Our data for the first time demonstrate that inhibition of the Nox-4-associated prosurvival signaling pathway by shikonin enhances the antiproliferative and antiangiogenic potential of 2-DG in GBM cells. CONCLUSION: In summary, the combined inhibition of Nox-4 and glycolysis may have therapeutic implications for the management of GBMs.
AIMS: 2-Deoxy-d-glucose (2-DG), a synthetic glycolytic inhibitor, is currently under clinical evaluation as a promising anticancer agent. However, 2-DG treatment in cancer cells activates prosurvival Akt signaling that might limit its clinical efficacy. The NADPH oxidase 4 (Nox-4)/reactive oxygen species/Akt signaling is known to regulate survival, proliferation, infiltration, and invasion in glioblastomas (GBMs). The enhanced motility, invasiveness, and therapy resistance in GBMs are attributed to metabolic adaptation through increased aerobic glycolysis. Therefore, we hypothesized that inhibition of the Nox-4 might enhance 2-DG-induced suppression of glycolysis, migration, and invasion in GBM cells. RESULTS: We identified the natural naphthoquinone compound shikonin as a potent inhibitor of the Nox-4/Akt signaling pathway. The combined treatment of shikonin+2-DG suppressed the glycolytic phenotype, migration, and invasion through modulation of the Akt/HIF1α/hexokinase-2 signaling axis in GBM cells. The combination also exhibited enhanced antiproliferative and antiangiogenic effects in vivo. INNOVATION: Our data for the first time demonstrate that inhibition of the Nox-4-associated prosurvival signaling pathway by shikonin enhances the antiproliferative and antiangiogenic potential of 2-DG in GBM cells. CONCLUSION: In summary, the combined inhibition of Nox-4 and glycolysis may have therapeutic implications for the management of GBMs.
Authors: G Teixeira; C Szyndralewiez; S Molango; S Carnesecchi; F Heitz; P Wiesel; J M Wood Journal: Br J Pharmacol Date: 2016-07-14 Impact factor: 8.739
Authors: Abinash Padhi; Alexander H Thomson; Justin B Perry; Grace N Davis; Ryan P McMillan; Sandra Loesgen; Elizabeth N Kaweesa; Rakesh Kapania; Amrinder S Nain; David A Brown Journal: Am J Physiol Cell Physiol Date: 2019-12-25 Impact factor: 4.249