Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition
2016
Аутори:
Kosić, MilicaArsikin-Csordas, Katarina
Paunović, Verica
Firestone, Raymond A
Ristić, Biljana
Mirčić, Aleksandar
Petričević, Saša
Bošnjak, Mihajlo
Zogović, Nevena
Mandić, Miloš
Bumbaširević, Vladimir
Trajković, Vladimir
Harhaji-Trajković, Ljubica
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
We investigated the in vitro and in vivo anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-D-glucose (2DG). NDI-triggered LMP and 2DG-me diated glycolysis block synergized in inducing rapid ATP
depletion, mitochondrial damage, and reactive oxygen species 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 a-tocopherol, suggesting the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agent chloroquine also displayed a synergistic anticancer effect with 2DG, whereas glucose deprivation or glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus further indicating that the anticancer
effect of NDI/2DG combination was indeed due to LMP and glycolysis block. The two agents synergistically induced ATP depletion, mitochondrial depolarization, oxidative stress, and necrotic death also in B16 mouse melanoma cells. Moreover, the combined oral administration of NDI and 2DG reduced in vivo melanoma growth in C57BL/6 mice by inducing necrotic death of tumor cells, without causing liver, spleen, or kidney toxicity. 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 reactive oxygen species 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:
anticancer therapy; glycolysis; mitochondrial damage; necrotic cell death; lysosomesИзвор:
Journal of Biological Chemistry, 2016, 291, 44, 22936-22948Финансирање / 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)
DOI: 10.1074/jbc.M116.752113
ISSN: 0021-9258
PubMed: 27587392