Synergistic anticancer action of lysosomal membrane permeabilization and glycolysis inhibition
2015
Аутори:
Kosić, MilicaArsikin-Csordas, Katarina
Paunović, Verica
Firestone, Raymond A
Ristić, Biljana
Mirčić, Aleksandar
Petričević, Saša
Bošnjak, Mihajlo
Zogović, Nevena
Bumbaširević, Vladimir
Trajković, Vladimir
Harhaji-Trajković, Ljubica
Остала ауторства
Korać, BatoStančić, Ana
Тип документа:
Конференцијски прилог (Објављена верзија)
,
© 2015 by the Serbian Society for Mitochondrial and Free-Radical Physiology
Метаподаци
Приказ свих података о документуАпстракт:
We investigated the in vitro anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-D-glucose (2DG). Cell viability was measured by MTT and LDH tests. Oxidative stress, lysosomal permeabilization, mitochondrial depolarization and apoptosis/necrosis were analyzed by flow cytometry. Cell morphology was examined by electron microscopy. Intracellular ATP content was measured by bioluminescence assay. NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial
damage, and reactive oxygen species (ROS) production, eventually leading to necrotic death
of U251 glioma cells, but not primary astrocytes. NDI/2DG-induced death of glioma cells was
partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, indicating the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agents chloroquine and NH4Cl also displayed synergistic anticancer effect with 2DG, while glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus confirming that the anticancer effect of NDI/2DG combination was indeed due to LMP and glycolysis block, respectively. Based on these results, we propose that NDI-triggered LMP causes initial mitochondrial damage that is further increased by 2DG due to the lack of glycolytic ATP required to maintain mitochondrial health. This leads to a positive
feedback cycle of mitochondrial dysfunction, ATP loss, and ROS production, culminating in necrotic cell death. Therefore, the combination of LMP-inducing agents and glycolysis inhibitors seems worthy of further exploration as an anticancer strategy.
Кључне речи:
antiglioma therapy; mitochondria damage; glycolysis; oxidative stress; necrotic cell deathФинансирање / пројекти:
- Улога аутофагије у регулацији смрти туморских ћелија (RS-MESTD-Basic Research (BR or ON)-173053)
- Модулација сигналних путева који контролишу интрацелуларни енергетски баланс у терапији тумора и неуро-имуно-ендокриних поремећаја (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41025)
У:
- Korać B, Stančić A, editors. Book of Abstracts: Third Congress Redox Medicine: Reactive Species Signaling, Analytical Methods, Phytopharmacy, Molecular Mechanisms of Disease - SSMFRP-2015; 2015 Sep 25-26; Belgrade, Serbia. Belgrade: Serbian Society for Mitochondrial and Free-Radical Physiology; 2015. p. 71.