TY  - CONF
AU  - Paunović, Verica
AU  - Misirkić Marjanović, Maja
AU  - Vučićević, Ljubica
AU  - Stevanović, Danijela
AU  - Ristić, Biljana
AU  - Bošnjak, Mihajlo
AU  - Mandić, Miloš
AU  - Trajković, Vladimir
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6570
AB  - Autophagy is a homeostatic lysosome-dependent catabolic process that eliminates damaged organelles, dysfunctional proteins, and macromolecular aggregates. Autophagy plays an important role in host response to viral infection as it enables degradation of viruses in autophagolysosomes and regulates innate and adaptive immunity. However, some viruses, including SARS-CoV-2, have evolved a variety of mechanisms to avoid autophagic degradation and use it for their own benefit. The aim of this study is to investigate the impact of the individual SARS-CoV-2 proteins (M, E, N, NSP4, NSP5, NSP6, NSP7, NSP8, NSP10, NSP12, NSP14, and NSP15) on autophagy in human lung epithelial cells by analyzing the expression of autophagy-related proteins, LC3-II, p62, and beclin1. The immunoblot analysis revealed that intracellular expression of non-structural proteins NSP4, NSP6, and NSP8 increased the levels of autophagy markers LC3-II and beclin-1, while the structural N protein and non-structural proteins NSP5, NSP10, and NSP15, reduced the degradation of autophagy-selective target p62. These data indicate that some SARS-CoV-2 proteins induce autophagic response, while others block its completion, thus providing grounds for further investigation of the complex interaction between the virus and the autophagic pathway.
AB  - Аутофагија је лизозомски посредован хомеостатски катаболички процес током којег долази до елиминисања оштећених органела, дисфункционалних протеина и макромолекуларних комплекса. Аутофагија игра важну улогу у одговору домаћина на вирусну инфекцију јер омогућава деградацију вируса у аутофаголизозомима и регулише урођени и стечени имунитет. Међутим, неки вируси, укључујући и SARS-CoV-2, су развили различите механизме како би избегли деградацију која се дешава током процеса аутофагије и подредили је у своју корист. Ова студија има за циљ да испита утицај појединачних SARS-CoV-2 протеина (M, E, N, NSP4, NSP5, NSP6, NSP7, NSP8, NSP10, NSP12, NSP14 и NSP15) на процес аутофагије који се одвија у ћелијама респираторног епитела код људи анализом експресије протеина повезаних са аутофагијом, LC3-II, p62, и беклин 1. Имуноблот анализа је открила да је унутарћелијска експресија неструктурних протеина NSP4, NSP6 и NSP8 повећала нивое маркера аутофагије LC3-II и беклин-1, док су структурни N протеин и неструктурни протеини NSP5, NSP10 и NSP15 довели до смањења деградације рецептора аутофагије p62. Ови подаци указују на то да неки SARS-CoV-2 протеини индукују аутофагни одговор, док други блокирају завршетак процеса аутофагије, чиме се ствара основа за даље истраживање комплексне интеракције између вируса и процеса аутофагије.
PB  - Beograd: Srpska akademija nauka i umetnosti
C3  - Proceedings: COVID-19 Pandemic: Messages, New Information and Dilemmas; 2021 Jun 4; Belgrade, Serbia
T1  - Modulation of autophagy by SARS-CoV-2 proteins
T1  - Модулација аутофагије SARS-CoV-2 протеинима
SP  - 205
EP  - 212
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6570
ER  - 

@conference{
author = "Paunović, Verica and Misirkić Marjanović, Maja and Vučićević, Ljubica and Stevanović, Danijela and Ristić, Biljana and Bošnjak, Mihajlo and Mandić, Miloš and Trajković, Vladimir",
year = "2022",
abstract = "Autophagy is a homeostatic lysosome-dependent catabolic process that eliminates damaged organelles, dysfunctional proteins, and macromolecular aggregates. Autophagy plays an important role in host response to viral infection as it enables degradation of viruses in autophagolysosomes and regulates innate and adaptive immunity. However, some viruses, including SARS-CoV-2, have evolved a variety of mechanisms to avoid autophagic degradation and use it for their own benefit. The aim of this study is to investigate the impact of the individual SARS-CoV-2 proteins (M, E, N, NSP4, NSP5, NSP6, NSP7, NSP8, NSP10, NSP12, NSP14, and NSP15) on autophagy in human lung epithelial cells by analyzing the expression of autophagy-related proteins, LC3-II, p62, and beclin1. The immunoblot analysis revealed that intracellular expression of non-structural proteins NSP4, NSP6, and NSP8 increased the levels of autophagy markers LC3-II and beclin-1, while the structural N protein and non-structural proteins NSP5, NSP10, and NSP15, reduced the degradation of autophagy-selective target p62. These data indicate that some SARS-CoV-2 proteins induce autophagic response, while others block its completion, thus providing grounds for further investigation of the complex interaction between the virus and the autophagic pathway., Аутофагија је лизозомски посредован хомеостатски катаболички процес током којег долази до елиминисања оштећених органела, дисфункционалних протеина и макромолекуларних комплекса. Аутофагија игра важну улогу у одговору домаћина на вирусну инфекцију јер омогућава деградацију вируса у аутофаголизозомима и регулише урођени и стечени имунитет. Међутим, неки вируси, укључујући и SARS-CoV-2, су развили различите механизме како би избегли деградацију која се дешава током процеса аутофагије и подредили је у своју корист. Ова студија има за циљ да испита утицај појединачних SARS-CoV-2 протеина (M, E, N, NSP4, NSP5, NSP6, NSP7, NSP8, NSP10, NSP12, NSP14 и NSP15) на процес аутофагије који се одвија у ћелијама респираторног епитела код људи анализом експресије протеина повезаних са аутофагијом, LC3-II, p62, и беклин 1. Имуноблот анализа је открила да је унутарћелијска експресија неструктурних протеина NSP4, NSP6 и NSP8 повећала нивое маркера аутофагије LC3-II и беклин-1, док су структурни N протеин и неструктурни протеини NSP5, NSP10 и NSP15 довели до смањења деградације рецептора аутофагије p62. Ови подаци указују на то да неки SARS-CoV-2 протеини индукују аутофагни одговор, док други блокирају завршетак процеса аутофагије, чиме се ствара основа за даље истраживање комплексне интеракције између вируса и процеса аутофагије.",
publisher = "Beograd: Srpska akademija nauka i umetnosti",
journal = "Proceedings: COVID-19 Pandemic: Messages, New Information and Dilemmas; 2021 Jun 4; Belgrade, Serbia",
title = "Modulation of autophagy by SARS-CoV-2 proteins, Модулација аутофагије SARS-CoV-2 протеинима",
pages = "205-212",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6570"
}

Paunović, V., Misirkić Marjanović, M., Vučićević, L., Stevanović, D., Ristić, B., Bošnjak, M., Mandić, M.,& Trajković, V.. (2022). Modulation of autophagy by SARS-CoV-2 proteins. in Proceedings: COVID-19 Pandemic: Messages, New Information and Dilemmas; 2021 Jun 4; Belgrade, Serbia
Beograd: Srpska akademija nauka i umetnosti., 205-212.
https://hdl.handle.net/21.15107/rcub_ibiss_6570

Paunović V, Misirkić Marjanović M, Vučićević L, Stevanović D, Ristić B, Bošnjak M, Mandić M, Trajković V. Modulation of autophagy by SARS-CoV-2 proteins. in Proceedings: COVID-19 Pandemic: Messages, New Information and Dilemmas; 2021 Jun 4; Belgrade, Serbia. 2022;:205-212.
https://hdl.handle.net/21.15107/rcub_ibiss_6570 .

Paunović, Verica, Misirkić Marjanović, Maja, Vučićević, Ljubica, Stevanović, Danijela, Ristić, Biljana, Bošnjak, Mihajlo, Mandić, Miloš, Trajković, Vladimir, "Modulation of autophagy by SARS-CoV-2 proteins" in Proceedings: COVID-19 Pandemic: Messages, New Information and Dilemmas; 2021 Jun 4; Belgrade, Serbia (2022):205-212,
https://hdl.handle.net/21.15107/rcub_ibiss_6570 .

TY  - CONF
AU  - Ristić, Biljana
AU  - Krunić, Matija
AU  - Bošnjak, Mihajlo
AU  - Mirčić, Aleksandar
AU  - Tovilović-Kovačević, Gordana
AU  - Zogović, Nevena
AU  - Paunović, Verica
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
PY  - 2019
UR  - https://nordicautophagy.org/
UR  - https://nordicautophagy.org/report-3rd-nordic-autophagy-society-conference-in-utrecht/
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6718
AB  - We investigated the ability of nano-sized graphen layers graphen quantum dots (GQD) to protect human neuroblastoma SH-SY5Y cells from toxicity of NO donor sodium nitroprusside (SNP). GQD prevented SNP induced mitochondrial depolarization and caspase dependent apoptosis. GQD partly suppressed neurotoxicity of NO donor DEA-NONOate and reduced SNP induced NO release in cells and cell-free system, suggesting that neuroprotective effects of GQD were partly mediated by their NO-scavanging capacity. However, GQD significantly preserved SH-SY5Y cells from light exhausted SNP, which was unable to produce NO, implying the existence of protective mechanism independent of NO-scavenging. Unspecific antioxidant, as well as hydroxyl radical (.OH) scavengers DMSO, vitamin E and gluthatione mimicked neuroprotective activity of GQD, while GQD diminished concentration of reactive oxygen species (ROS), especially .OH, in cells and cell culture medium, suggesting important role of .OH scavenging in neuroprotective activity of GQD. However ability of GQD to protect SH-SY5Y cells from SNP was not exclusively mediated by their ability to scavenge NO and ROS from medium, since it persisted after washing of GQD preincubated cells. Interestingly, GQD were found to be present in autophagosome-like vacuoles. Both SNP and GQD, and especially their combination, increased intracellular acidity characteristic for presence of autophagosomes, concentration of proautophagic protein beclin-1, while deacreased level of specific substrate of autophagic proteolysis p62. Moreover, SNP and GQD, and above all their combination, increased concentration of autophagosome-associated protein LC3 II in the presence of inhibitor of autophagic proteolysis bafilomycin A1. Finally, autophagy inhibitors 3-methzladenine, wortmannin and NH4Cl prevented neuroprotective ability of GQD, implying that GQD stimulated prosurvival autophagy in SNP treated neurons. Therefore, by demonstrating ability of GQD to protect SH-SY5Y neurons from SNP induced apoptosis by scavenging NO/ROS and stimulation of cytoprotective autophagy, our results suggest that GQD could be valuable candidate for treatment of neurodegenerative disorders.
PB  - Nordic Autophagy Society
C3  - 3rd Nordic Autophagy Society (NAS) Conference; 2019 May 22-24; Utrecht, Netherlands
T1  - Neuroprotective activity of GQD against SNP-induced toxicity are mediated by ROS/RNS scavenging and protective autophagy induction
SP  - 40
EP  - 40
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6718
ER  - 

@conference{
author = "Ristić, Biljana and Krunić, Matija and Bošnjak, Mihajlo and Mirčić, Aleksandar and Tovilović-Kovačević, Gordana and Zogović, Nevena and Paunović, Verica and Trajković, Vladimir and Harhaji-Trajković, Ljubica",
year = "2019",
abstract = "We investigated the ability of nano-sized graphen layers graphen quantum dots (GQD) to protect human neuroblastoma SH-SY5Y cells from toxicity of NO donor sodium nitroprusside (SNP). GQD prevented SNP induced mitochondrial depolarization and caspase dependent apoptosis. GQD partly suppressed neurotoxicity of NO donor DEA-NONOate and reduced SNP induced NO release in cells and cell-free system, suggesting that neuroprotective effects of GQD were partly mediated by their NO-scavanging capacity. However, GQD significantly preserved SH-SY5Y cells from light exhausted SNP, which was unable to produce NO, implying the existence of protective mechanism independent of NO-scavenging. Unspecific antioxidant, as well as hydroxyl radical (.OH) scavengers DMSO, vitamin E and gluthatione mimicked neuroprotective activity of GQD, while GQD diminished concentration of reactive oxygen species (ROS), especially .OH, in cells and cell culture medium, suggesting important role of .OH scavenging in neuroprotective activity of GQD. However ability of GQD to protect SH-SY5Y cells from SNP was not exclusively mediated by their ability to scavenge NO and ROS from medium, since it persisted after washing of GQD preincubated cells. Interestingly, GQD were found to be present in autophagosome-like vacuoles. Both SNP and GQD, and especially their combination, increased intracellular acidity characteristic for presence of autophagosomes, concentration of proautophagic protein beclin-1, while deacreased level of specific substrate of autophagic proteolysis p62. Moreover, SNP and GQD, and above all their combination, increased concentration of autophagosome-associated protein LC3 II in the presence of inhibitor of autophagic proteolysis bafilomycin A1. Finally, autophagy inhibitors 3-methzladenine, wortmannin and NH4Cl prevented neuroprotective ability of GQD, implying that GQD stimulated prosurvival autophagy in SNP treated neurons. Therefore, by demonstrating ability of GQD to protect SH-SY5Y neurons from SNP induced apoptosis by scavenging NO/ROS and stimulation of cytoprotective autophagy, our results suggest that GQD could be valuable candidate for treatment of neurodegenerative disorders.",
publisher = "Nordic Autophagy Society",
journal = "3rd Nordic Autophagy Society (NAS) Conference; 2019 May 22-24; Utrecht, Netherlands",
title = "Neuroprotective activity of GQD against SNP-induced toxicity are mediated by ROS/RNS scavenging and protective autophagy induction",
pages = "40-40",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6718"
}

Ristić, B., Krunić, M., Bošnjak, M., Mirčić, A., Tovilović-Kovačević, G., Zogović, N., Paunović, V., Trajković, V.,& Harhaji-Trajković, L.. (2019). Neuroprotective activity of GQD against SNP-induced toxicity are mediated by ROS/RNS scavenging and protective autophagy induction. in 3rd Nordic Autophagy Society (NAS) Conference; 2019 May 22-24; Utrecht, Netherlands
Nordic Autophagy Society., 40-40.
https://hdl.handle.net/21.15107/rcub_ibiss_6718

Ristić B, Krunić M, Bošnjak M, Mirčić A, Tovilović-Kovačević G, Zogović N, Paunović V, Trajković V, Harhaji-Trajković L. Neuroprotective activity of GQD against SNP-induced toxicity are mediated by ROS/RNS scavenging and protective autophagy induction. in 3rd Nordic Autophagy Society (NAS) Conference; 2019 May 22-24; Utrecht, Netherlands. 2019;:40-40.
https://hdl.handle.net/21.15107/rcub_ibiss_6718 .

Ristić, Biljana, Krunić, Matija, Bošnjak, Mihajlo, Mirčić, Aleksandar, Tovilović-Kovačević, Gordana, Zogović, Nevena, Paunović, Verica, Trajković, Vladimir, Harhaji-Trajković, Ljubica, "Neuroprotective activity of GQD against SNP-induced toxicity are mediated by ROS/RNS scavenging and protective autophagy induction" in 3rd Nordic Autophagy Society (NAS) Conference; 2019 May 22-24; Utrecht, Netherlands (2019):40-40,
https://hdl.handle.net/21.15107/rcub_ibiss_6718 .

TY  - CONF
AU  - Bošnjak, Mihajlo
AU  - Ristić, Biljana
AU  - Krunić, Matija
AU  - Mirčić, Aleksandar
AU  - Zogović, Nevena
AU  - Tovilović-Kovačević, Gordana
AU  - Paunović, Verica
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6341
AB  - We here investigated protective potential of nanoparticles graphene quantum dots
(GQD) against neurotoxicity of sodium nitroprusside (SNP), NO-donor and
antihypertensive drug widely used in studies of nitrosative stress-induced
neurotoxicity. GQD prevented SNP-induced apoptosis, caspase activation and
mitochondrial depolarization in SH-SY5Y neuroblastoma cells. GQD decreased SNP
generated nitrite accumulation in supernatants, as well as NO/ONOO- concentrations
in cells and cell-free medium. However, ONOO- and NO scavengers only slightly
suppressed SNP neurotoxicity. Moreover, light exhausted SNP, incapable of producing
NO, was toxic to SH-SY5Y cells, while GQD strongly reduced its neurotoxicity,
suggesting that defensive effect of GQD far exceeded their NO scavenging activity.
FeSO4 increased death of SH-SY5Y cells, while iron chelators decreased toxicity of
iron-containing SNP. GQD neutralized SNP generated reactive oxygen species (ROS)
production, particularly O2•− and •OH in both cells and cell-free condition.
Neurotoxicity of SNP was suppressed in the presence of unspecific antioxidants,
scavengers of •OH and lipid hydroperoxyl radicals, while it was increased with •OH
generating superoxide dismutase (SOD). Intracellular localization of GQD was
confirmed by transmission electron microscopy (TEM), while extensive washing of
cells preincubated with GQD, only partly reduced their protective activity, suggesting
that GQD exerted neuroprotective effect both intra- and extracellularly. Taken together,
these results suggested that GQD protected neuroblastoma cells by neutralizing reactive
nitrogen species (RNS) and ROS, predominantly •OH formed in Fenton reaction
catalyzed by iron derived from SNP. Therefore, GQD might be promising choice for
treatment of ROS/RNS-mediated neurodegenerative diseases.
PB  - Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade
C3  - Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia
T1  - Graphene quantum dots protect SH-SY5Y cells from SNP induced apoptosis by scavenging reactive oxygen and nitrogen species
SP  - 37
EP  - 37
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6341
ER  - 

@conference{
author = "Bošnjak, Mihajlo and Ristić, Biljana and Krunić, Matija and Mirčić, Aleksandar and Zogović, Nevena and Tovilović-Kovačević, Gordana and Paunović, Verica and Trajković, Vladimir and Harhaji-Trajković, Ljubica",
year = "2019",
abstract = "We here investigated protective potential of nanoparticles graphene quantum dots
(GQD) against neurotoxicity of sodium nitroprusside (SNP), NO-donor and
antihypertensive drug widely used in studies of nitrosative stress-induced
neurotoxicity. GQD prevented SNP-induced apoptosis, caspase activation and
mitochondrial depolarization in SH-SY5Y neuroblastoma cells. GQD decreased SNP
generated nitrite accumulation in supernatants, as well as NO/ONOO- concentrations
in cells and cell-free medium. However, ONOO- and NO scavengers only slightly
suppressed SNP neurotoxicity. Moreover, light exhausted SNP, incapable of producing
NO, was toxic to SH-SY5Y cells, while GQD strongly reduced its neurotoxicity,
suggesting that defensive effect of GQD far exceeded their NO scavenging activity.
FeSO4 increased death of SH-SY5Y cells, while iron chelators decreased toxicity of
iron-containing SNP. GQD neutralized SNP generated reactive oxygen species (ROS)
production, particularly O2•− and •OH in both cells and cell-free condition.
Neurotoxicity of SNP was suppressed in the presence of unspecific antioxidants,
scavengers of •OH and lipid hydroperoxyl radicals, while it was increased with •OH
generating superoxide dismutase (SOD). Intracellular localization of GQD was
confirmed by transmission electron microscopy (TEM), while extensive washing of
cells preincubated with GQD, only partly reduced their protective activity, suggesting
that GQD exerted neuroprotective effect both intra- and extracellularly. Taken together,
these results suggested that GQD protected neuroblastoma cells by neutralizing reactive
nitrogen species (RNS) and ROS, predominantly •OH formed in Fenton reaction
catalyzed by iron derived from SNP. Therefore, GQD might be promising choice for
treatment of ROS/RNS-mediated neurodegenerative diseases.",
publisher = "Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade",
journal = "Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia",
title = "Graphene quantum dots protect SH-SY5Y cells from SNP induced apoptosis by scavenging reactive oxygen and nitrogen species",
pages = "37-37",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6341"
}

Bošnjak, M., Ristić, B., Krunić, M., Mirčić, A., Zogović, N., Tovilović-Kovačević, G., Paunović, V., Trajković, V.,& Harhaji-Trajković, L.. (2019). Graphene quantum dots protect SH-SY5Y cells from SNP induced apoptosis by scavenging reactive oxygen and nitrogen species. in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia
Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade., 37-37.
https://hdl.handle.net/21.15107/rcub_ibiss_6341

Bošnjak M, Ristić B, Krunić M, Mirčić A, Zogović N, Tovilović-Kovačević G, Paunović V, Trajković V, Harhaji-Trajković L. Graphene quantum dots protect SH-SY5Y cells from SNP induced apoptosis by scavenging reactive oxygen and nitrogen species. in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia. 2019;:37-37.
https://hdl.handle.net/21.15107/rcub_ibiss_6341 .

Bošnjak, Mihajlo, Ristić, Biljana, Krunić, Matija, Mirčić, Aleksandar, Zogović, Nevena, Tovilović-Kovačević, Gordana, Paunović, Verica, Trajković, Vladimir, Harhaji-Trajković, Ljubica, "Graphene quantum dots protect SH-SY5Y cells from SNP induced apoptosis by scavenging reactive oxygen and nitrogen species" in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia (2019):37-37,
https://hdl.handle.net/21.15107/rcub_ibiss_6341 .

TY  - JOUR
AU  - Kosić, Milica
AU  - Arsikin-Csordas, Katarina
AU  - Paunović, Verica
AU  - Firestone, Raymond A
AU  - Ristić, Biljana
AU  - Mirčić, Aleksandar
AU  - Petričević, Saša
AU  - Bošnjak, Mihajlo
AU  - Zogović, Nevena
AU  - Mandić, Miloš
AU  - Bumbaširević, Vladimir
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
PY  - 2016
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6364
AB  - 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.
PB  - Amsterdam: Elsevier
T2  - Journal of Biological Chemistry
T1  - Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition
IS  - 44
VL  - 291
DO  - 10.1074/jbc.M116.752113
SP  - 22936
EP  - 22948
ER  - 

@article{
author = "Kosić, Milica and Arsikin-Csordas, Katarina and Paunović, Verica and Firestone, Raymond A and Ristić, Biljana and Mirčić, Aleksandar and Petričević, Saša and Bošnjak, Mihajlo and Zogović, Nevena and Mandić, Miloš and Bumbaširević, Vladimir and Trajković, Vladimir and Harhaji-Trajković, Ljubica",
year = "2016",
abstract = "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.",
publisher = "Amsterdam: Elsevier",
journal = "Journal of Biological Chemistry",
title = "Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition",
number = "44",
volume = "291",
doi = "10.1074/jbc.M116.752113",
pages = "22936-22948"
}

Kosić, M., Arsikin-Csordas, K., Paunović, V., Firestone, R. A., Ristić, B., Mirčić, A., Petričević, S., Bošnjak, M., Zogović, N., Mandić, M., Bumbaširević, V., Trajković, V.,& Harhaji-Trajković, L.. (2016). Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition. in Journal of Biological Chemistry
Amsterdam: Elsevier., 291(44), 22936-22948.
https://doi.org/10.1074/jbc.M116.752113

Kosić M, Arsikin-Csordas K, Paunović V, Firestone RA, Ristić B, Mirčić A, Petričević S, Bošnjak M, Zogović N, Mandić M, Bumbaširević V, Trajković V, Harhaji-Trajković L. Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition. in Journal of Biological Chemistry. 2016;291(44):22936-22948.
doi:10.1074/jbc.M116.752113 .

Kosić, Milica, Arsikin-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, "Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition" in Journal of Biological Chemistry, 291, no. 44 (2016):22936-22948,
https://doi.org/10.1074/jbc.M116.752113 . .