Synergistic anticancer effect of glycolysis inhibition and oxidative phosphorylation suppression
2021
Аутори:
Kosić, MilicaPaunović, Verica
Ristić, Biljana
Mirčić, Aleksandar
Bošnjak, Mihajlo
Stevanović, Danijela
Mandić, Miloš
Stamenković, Marina
Janjetović, Kristina
Vučićević, Ljubica
Trajković, Vladimir
Harhaji-Trajković, Ljubica
Тип документа:
Конференцијски прилог (Објављена верзија)
,
© 2021 Published by Elsevier Inc.
Метаподаци
Приказ свих података о документуАпстракт:
There is no effective therapy for melanoma, a malignant tumor of melanocytes with an
increasing incidence. High energy demands of melanoma cells are predominantly satisfied by
aerobic glycolysis. When glycolysis is suppressed, these metabolically plastic cells switch to
oxidative phosphorylation. The aim of this study was to investigate the antimelanoma effects of
simultaneous inhibition of glycolysis by 2-deoxy-D-glucose (2DG) and oxidative phosphorylation
by rotenone (ROT). 2DG synergized with ROT in inducing death of B16 melanoma, but not
primary mesenchymal cells. Combined treatment stimulated caspase activation, but not PARP
cleavage and DNA fragmentation. Disintegration of plasma membrane and inability of caspase
inhibitors and necrostatin to suppress toxicity of 2DG/ROT implied that combined treatment
induced necrosis, rather than apoptosis and necroptosis. 2DG/ROT stimulated ATP depletion,
mitochondrial superoxide production, and mitochondrial swelling, but not depolarization
of mitochondria. 2DG/ROT-induced toxicity was suppressed by antioxidant α-tocopherol,
but not mitochondrial depolarization inhibitor cyclosporine. Combined treatment induced
the translocation of hexokinase II, a suppressor of voltage-dependent anion channel (VDAC)
opening, and cytochrome c from mitochondria in the cytoplasm, while VDAC opening inhibitor
DIDS suppressed 2DG/ROT toxicity. Our results suggest that 2DG/ROT treatment stimulates
mitochondrial swelling, release of hexokinase II and subsequent opening of VDAC in the outer
mitochondrial membrane. These events allow cytochrome c to exit and activate caspases, which
are unable to stimulate PARP and consequent DNA fragmentation in the energy-depleted state.
On the other hand, superoxide synthesized in mitochondria upon 2DG/ROT treatment also exits
through VDAC and triggers energy-independent necrosis. Simultaneous inhibition of glycolysis
and oxidative phosphorylation appears to be promising strategy for further development of
novel anticancer therapeutics.
Кључне речи:
glycolysis; oxidative phosphorylation; mitochondria; necrosis; 2-deoxy-D-glucose; rotenone; antitumor therapy; melanomaУ:
- Free Radical Research Europe (SFRR-E): Annual Meeting Abstracts: “Redox biology in the 21st century: a new scientific discipline”; 2021 Jun 15-18; Belgrade, Serbia. Elsevier; 2021. p. S125. (Free Radical Biology and Medicine; Vol. 177; Suppl. 1).