TY  - JOUR
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Janjetović, Kristina
AU  - Vilimanović, Uros
AU  - Sudar, Emina M
AU  - Isenović, Esma R
AU  - Prica, Marko
AU  - Harhaji-Trajković, Ljubica
AU  - Kravić-Stevović, Tamara K
AU  - Bumbaširević, Vladimir Z
AU  - Trajković, Vladimir S
PY  - 2011
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1321
AB  - In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AICAR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential anticancer agents.
T2  - Autophagy
T1  - Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway
IS  - 1
VL  - 7
DO  - 10.4161/auto.7.1.13883
EP  - 50
ER  - 

@article{
author = "Vučićević, Ljubica and Misirkić Marjanović, Maja and Janjetović, Kristina and Vilimanović, Uros and Sudar, Emina M and Isenović, Esma R and Prica, Marko and Harhaji-Trajković, Ljubica and Kravić-Stevović, Tamara K and Bumbaširević, Vladimir Z and Trajković, Vladimir S",
year = "2011",
abstract = "In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AICAR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential anticancer agents.",
journal = "Autophagy",
title = "Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway",
number = "1",
volume = "7",
doi = "10.4161/auto.7.1.13883",
pages = "50"
}

Vučićević, L., Misirkić Marjanović, M., Janjetović, K., Vilimanović, U., Sudar, E. M., Isenović, E. R., Prica, M., Harhaji-Trajković, L., Kravić-Stevović, T. K., Bumbaširević, V. Z.,& Trajković, V. S.. (2011). Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. in Autophagy, 7(1).
https://doi.org/10.4161/auto.7.1.13883

Vučićević L, Misirkić Marjanović M, Janjetović K, Vilimanović U, Sudar EM, Isenović ER, Prica M, Harhaji-Trajković L, Kravić-Stevović TK, Bumbaširević VZ, Trajković VS. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. in Autophagy. 2011;7(1):null-50.
doi:10.4161/auto.7.1.13883 .

Vučićević, Ljubica, Misirkić Marjanović, Maja, Janjetović, Kristina, Vilimanović, Uros, Sudar, Emina M, Isenović, Esma R, Prica, Marko, Harhaji-Trajković, Ljubica, Kravić-Stevović, Tamara K, Bumbaširević, Vladimir Z, Trajković, Vladimir S, "Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway" in Autophagy, 7, no. 1 (2011),
https://doi.org/10.4161/auto.7.1.13883 . .

TY  - JOUR
AU  - Harhaji-Trajković, Ljubica
AU  - Vilimanovich, Urosh
AU  - Kravić-Stevović, Tamara
AU  - Bumbaširević, Vladimir
AU  - Trajković, Vladimir
PY  - 2009
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6547
AB  - The role of autophagy in cisplatin anticancer action was investigated using human U251 glioma, rat C6 glioma and mouse L929 fibrosarcoma cell lines. A dose- and time-dependent induction of autophagy was observed in tumour cells following cisplatin treatment, as demonstrated by up-regulation of autophagy-inducing protein beclin-1 and subsequent appearance of acridine orange-stained acidic autophagic vesicles. The presence of autophagosomes in cisplatin-treated cells was also confirmed by electron microscopy. Inhibition of autophagy with lysosomal inhibitors bafilomycin A1 and chloroquine, or a PI3 kinase inhibitor wortmannin, markedly augmented cisplatin-triggered oxidative stress and caspase activation, leading to an increase in DNA fragmentation and apoptotic cell death. The mechanisms underlying the protective effect of autophagy apparently involved the interference with cisplatin-induced modulation of Bcl-2 family proteins, as inhibition of autophagy potentiated cisplatin-mediated up-regulation of proapoptotic Bax and down-regulation of anti-apoptotic Bcl-2. Autophagy induction in cisplatin-treated cells was preceded by activation of adenosine monophosphate-activated protein kinase (AMPK) and concomitant down-regulation of mammalian target of rapamycin (mTOR)-mediated phosphorylation of p70S6 kinase. The ability of cisplatin to trigger autophagy was reduced by small interfering RNA (siRNA)-mediated AMPK silencing, while transfection with mTOR siRNA was sufficient to trigger autophagy in tumour cells. Finally, siRNA-mediated AMPK down-regulation and AMPK inhibitor compound C increased cisplatin-induced tumour cell death, while mTOR siRNA and AMPK activator metformin protected tumour cells from cisplatin. Taken together, these data suggest that cisplatin-triggered activation of AMPK and subsequent suppression of mTOR activity can induce an autophagic response that protects tumour cells from cisplatin-mediated apoptotic death.
PB  - Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
T2  - Journal of Cellular and Molecular Medicine
T1  - AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells
IS  - 9B
VL  - 13
DO  - 10.1111/j.1582-4934.2009.00663.x
SP  - 3644
EP  - 3654
ER  - 

@article{
author = "Harhaji-Trajković, Ljubica and Vilimanovich, Urosh and Kravić-Stevović, Tamara and Bumbaširević, Vladimir and Trajković, Vladimir",
year = "2009",
abstract = "The role of autophagy in cisplatin anticancer action was investigated using human U251 glioma, rat C6 glioma and mouse L929 fibrosarcoma cell lines. A dose- and time-dependent induction of autophagy was observed in tumour cells following cisplatin treatment, as demonstrated by up-regulation of autophagy-inducing protein beclin-1 and subsequent appearance of acridine orange-stained acidic autophagic vesicles. The presence of autophagosomes in cisplatin-treated cells was also confirmed by electron microscopy. Inhibition of autophagy with lysosomal inhibitors bafilomycin A1 and chloroquine, or a PI3 kinase inhibitor wortmannin, markedly augmented cisplatin-triggered oxidative stress and caspase activation, leading to an increase in DNA fragmentation and apoptotic cell death. The mechanisms underlying the protective effect of autophagy apparently involved the interference with cisplatin-induced modulation of Bcl-2 family proteins, as inhibition of autophagy potentiated cisplatin-mediated up-regulation of proapoptotic Bax and down-regulation of anti-apoptotic Bcl-2. Autophagy induction in cisplatin-treated cells was preceded by activation of adenosine monophosphate-activated protein kinase (AMPK) and concomitant down-regulation of mammalian target of rapamycin (mTOR)-mediated phosphorylation of p70S6 kinase. The ability of cisplatin to trigger autophagy was reduced by small interfering RNA (siRNA)-mediated AMPK silencing, while transfection with mTOR siRNA was sufficient to trigger autophagy in tumour cells. Finally, siRNA-mediated AMPK down-regulation and AMPK inhibitor compound C increased cisplatin-induced tumour cell death, while mTOR siRNA and AMPK activator metformin protected tumour cells from cisplatin. Taken together, these data suggest that cisplatin-triggered activation of AMPK and subsequent suppression of mTOR activity can induce an autophagic response that protects tumour cells from cisplatin-mediated apoptotic death.",
publisher = "Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd",
journal = "Journal of Cellular and Molecular Medicine",
title = "AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells",
number = "9B",
volume = "13",
doi = "10.1111/j.1582-4934.2009.00663.x",
pages = "3644-3654"
}

Harhaji-Trajković, L., Vilimanovich, U., Kravić-Stevović, T., Bumbaširević, V.,& Trajković, V.. (2009). AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. in Journal of Cellular and Molecular Medicine
Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd., 13(9B), 3644-3654.
https://doi.org/10.1111/j.1582-4934.2009.00663.x

Harhaji-Trajković L, Vilimanovich U, Kravić-Stevović T, Bumbaširević V, Trajković V. AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. in Journal of Cellular and Molecular Medicine. 2009;13(9B):3644-3654.
doi:10.1111/j.1582-4934.2009.00663.x .

Harhaji-Trajković, Ljubica, Vilimanovich, Urosh, Kravić-Stevović, Tamara, Bumbaširević, Vladimir, Trajković, Vladimir, "AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells" in Journal of Cellular and Molecular Medicine, 13, no. 9B (2009):3644-3654,
https://doi.org/10.1111/j.1582-4934.2009.00663.x . .

TY  - JOUR
AU  - Isaković, Aleksandra
AU  - Harhaji-Trajković, Ljubica
AU  - Dacević, Mirjana
AU  - Trajković, Vladimir
PY  - 2008
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6546
AB  - We investigated the influence of adenosine on inducible nitric oxide (NO) synthase (iNOS)-dependent NO synthesis and viability of cytokine-treated C6 rat glioma cells. Adenosine significantly inhibited interferon-gamma (IFN-gamma)+interleukin-1beta (IL-1beta)-induced synthesis of iNOS mRNA/protein and subsequent production of NO in C6 cells. The uptake of adenosine into glioma cells was not required for the suppression of iNOS induction, as confirmed by the inability of the adenosine transport blocker nitrobenzylthyoinosine to block the observed effect. Adenosine also blocked the IFN-gamma+IL-1beta-triggered expression of mRNA for the proinflammatory cytokine TNF-alpha, while it significantly enhanced the accumulation of cyclooxygenase-2 (COX-2) mRNA in glioma cells. However, blockade of TNF-alpha action and COX-2 activity with anti-TNF-alpha antibodies and indomethacin, respectively, revealed that modulation of TNF-alpha and COX-2 was not involved in adenosine-mediated iNOS suppression. Adenosine significantly inhibited cytokine-induced activation of mitogen-activated protein kinase (MAPK) family members p38 MAPK, p42/44 MAPK and c-Jun N-terminal kinase (JNK) in C6 cells. The levels of transcription factors IRF-1 and c-Fos, as well as the phosphorylation of c-Jun were also reduced in adenosine-treated C6 cells, while the activation of NF-kappaB was enhanced via increased phosphorylation of its inhibitory unit IkappaB. Importantly, adenosine-mediated suppression of NO release rescued glioma cells from NO-dependent cytokine cytotoxicity. These data suggest a possible role for adenosine-mediated inhibition of glial NO synthesis in regulation of the inflammatory CNS damage and brain cancer progression.
PB  - Elsevier BV
T2  - European Journal of Pharmacology
T1  - Adenosine rescues glioma cells from cytokine-induced death by interfering with the signaling network involved in nitric oxide production
IS  - 1-3
VL  - 591
DO  - 10.1016/j.ejphar.2008.06.076
SP  - 106
EP  - 113
ER  - 

@article{
author = "Isaković, Aleksandra and Harhaji-Trajković, Ljubica and Dacević, Mirjana and Trajković, Vladimir",
year = "2008",
abstract = "We investigated the influence of adenosine on inducible nitric oxide (NO) synthase (iNOS)-dependent NO synthesis and viability of cytokine-treated C6 rat glioma cells. Adenosine significantly inhibited interferon-gamma (IFN-gamma)+interleukin-1beta (IL-1beta)-induced synthesis of iNOS mRNA/protein and subsequent production of NO in C6 cells. The uptake of adenosine into glioma cells was not required for the suppression of iNOS induction, as confirmed by the inability of the adenosine transport blocker nitrobenzylthyoinosine to block the observed effect. Adenosine also blocked the IFN-gamma+IL-1beta-triggered expression of mRNA for the proinflammatory cytokine TNF-alpha, while it significantly enhanced the accumulation of cyclooxygenase-2 (COX-2) mRNA in glioma cells. However, blockade of TNF-alpha action and COX-2 activity with anti-TNF-alpha antibodies and indomethacin, respectively, revealed that modulation of TNF-alpha and COX-2 was not involved in adenosine-mediated iNOS suppression. Adenosine significantly inhibited cytokine-induced activation of mitogen-activated protein kinase (MAPK) family members p38 MAPK, p42/44 MAPK and c-Jun N-terminal kinase (JNK) in C6 cells. The levels of transcription factors IRF-1 and c-Fos, as well as the phosphorylation of c-Jun were also reduced in adenosine-treated C6 cells, while the activation of NF-kappaB was enhanced via increased phosphorylation of its inhibitory unit IkappaB. Importantly, adenosine-mediated suppression of NO release rescued glioma cells from NO-dependent cytokine cytotoxicity. These data suggest a possible role for adenosine-mediated inhibition of glial NO synthesis in regulation of the inflammatory CNS damage and brain cancer progression.",
publisher = "Elsevier BV",
journal = "European Journal of Pharmacology",
title = "Adenosine rescues glioma cells from cytokine-induced death by interfering with the signaling network involved in nitric oxide production",
number = "1-3",
volume = "591",
doi = "10.1016/j.ejphar.2008.06.076",
pages = "106-113"
}

Isaković, A., Harhaji-Trajković, L., Dacević, M.,& Trajković, V.. (2008). Adenosine rescues glioma cells from cytokine-induced death by interfering with the signaling network involved in nitric oxide production. in European Journal of Pharmacology
Elsevier BV., 591(1-3), 106-113.
https://doi.org/10.1016/j.ejphar.2008.06.076

Isaković A, Harhaji-Trajković L, Dacević M, Trajković V. Adenosine rescues glioma cells from cytokine-induced death by interfering with the signaling network involved in nitric oxide production. in European Journal of Pharmacology. 2008;591(1-3):106-113.
doi:10.1016/j.ejphar.2008.06.076 .

Isaković, Aleksandra, Harhaji-Trajković, Ljubica, Dacević, Mirjana, Trajković, Vladimir, "Adenosine rescues glioma cells from cytokine-induced death by interfering with the signaling network involved in nitric oxide production" in European Journal of Pharmacology, 591, no. 1-3 (2008):106-113,
https://doi.org/10.1016/j.ejphar.2008.06.076 . .

TY  - JOUR
AU  - Janjetović, Kristina
AU  - Misirkić Marjanović, Maja
AU  - Vučićević, Ljubica
AU  - Harhaji-Trajković, Ljubica
AU  - Trajković, Vladimir
PY  - 2008
UR  - 2-s2.0-39749127025
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6545
AB  - To explore combined antiglioma effect of nitric oxide (NO) and hyperthermia, the rat C6 and human U251 glioma cells were exposed to NO-releasing agents sodium nitroprusside(SNP), S-nitrosoglutathione or PAPA-NONOate, followed by hyperthermia (1 h, 43 degrees C). While each treatment alone showed only moderate efficiency, a synergistic cytotoxicity of NO donors and hyperthermia was clearly demonstrated by crystal violet and MTT cytotoxicity assays. The flow cytometric analysis with the appropriate reporter fluorochromes confirmed that hyperthermia and SNP cooperated in inducing oxidative stress, mitochondrial depolarization, caspase activation and DNA fragmentation, leading to both necrotic and caspase-dependent apoptotic cell death. The acridine orange staining of intracellular acidic compartments revealed that SNP completely blocked hyperthermia-induced autophagy, while the inhibition of autophagy by 3-methyl adenine mimicked SNP-triggered oxidative stress, caspase activation and cell death in hyperthermia-exposed cells. Therefore, the synergistic cytotoxicity of SNP and hyperthermia could result from NO-mediated suppression of protective autophagic response in glioma cells.
PB  - Elsevier BV
T2  - European Journal of Pharmacology
T1  - Synergistic antiglioma action of hyperthermia and nitric oxide
IS  - 1
VL  - 583
DO  - 10.1016/j.ejphar.2007.12.028
SP  - 1
EP  - 10
ER  - 

@article{
author = "Janjetović, Kristina and Misirkić Marjanović, Maja and Vučićević, Ljubica and Harhaji-Trajković, Ljubica and Trajković, Vladimir",
year = "2008",
abstract = "To explore combined antiglioma effect of nitric oxide (NO) and hyperthermia, the rat C6 and human U251 glioma cells were exposed to NO-releasing agents sodium nitroprusside(SNP), S-nitrosoglutathione or PAPA-NONOate, followed by hyperthermia (1 h, 43 degrees C). While each treatment alone showed only moderate efficiency, a synergistic cytotoxicity of NO donors and hyperthermia was clearly demonstrated by crystal violet and MTT cytotoxicity assays. The flow cytometric analysis with the appropriate reporter fluorochromes confirmed that hyperthermia and SNP cooperated in inducing oxidative stress, mitochondrial depolarization, caspase activation and DNA fragmentation, leading to both necrotic and caspase-dependent apoptotic cell death. The acridine orange staining of intracellular acidic compartments revealed that SNP completely blocked hyperthermia-induced autophagy, while the inhibition of autophagy by 3-methyl adenine mimicked SNP-triggered oxidative stress, caspase activation and cell death in hyperthermia-exposed cells. Therefore, the synergistic cytotoxicity of SNP and hyperthermia could result from NO-mediated suppression of protective autophagic response in glioma cells.",
publisher = "Elsevier BV",
journal = "European Journal of Pharmacology",
title = "Synergistic antiglioma action of hyperthermia and nitric oxide",
number = "1",
volume = "583",
doi = "10.1016/j.ejphar.2007.12.028",
pages = "1-10"
}

Janjetović, K., Misirkić Marjanović, M., Vučićević, L., Harhaji-Trajković, L.,& Trajković, V.. (2008). Synergistic antiglioma action of hyperthermia and nitric oxide. in European Journal of Pharmacology
Elsevier BV., 583(1), 1-10.
https://doi.org/10.1016/j.ejphar.2007.12.028

Janjetović K, Misirkić Marjanović M, Vučićević L, Harhaji-Trajković L, Trajković V. Synergistic antiglioma action of hyperthermia and nitric oxide. in European Journal of Pharmacology. 2008;583(1):1-10.
doi:10.1016/j.ejphar.2007.12.028 .

Janjetović, Kristina, Misirkić Marjanović, Maja, Vučićević, Ljubica, Harhaji-Trajković, Ljubica, Trajković, Vladimir, "Synergistic antiglioma action of hyperthermia and nitric oxide" in European Journal of Pharmacology, 583, no. 1 (2008):1-10,
https://doi.org/10.1016/j.ejphar.2007.12.028 . .

TY  - JOUR
AU  - Isaković, Aleksandra
AU  - Marković, Zoran
AU  - Todorović-Marković, Biljana
AU  - Nikolić, Nadežda
AU  - Vranješ-Đurić, Sanja
AU  - Mirković, Marija
AU  - Dramićanin, Miroslav
AU  - Harhaji-Trajković, Ljubica
AU  - Zogović, Nevena
AU  - Nikolić, Zoran
AU  - Trajković, Vladimir
PY  - 2006
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3589
AB  - The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C 60 ) and water-soluble polyhydroxylated fullerene [C 60 (OH) n ] were investigated. Crystal violet assay for cell viability demonstrated that nano-C 60 was at least three orders of magnitude more toxic than C 60 (OH) n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C 60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C 60 (OH) n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C 60 toxicity, but not C 60 (OH) n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C 60 (OH) n -induced apoptosis, but not nano-C 60 -mediated necrosis. Finally, C 60 (OH) n antagomozed, while nano-C 60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C 60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C 60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.
PB  - Oxford University Press (OUP)
T2  - Toxicological Sciences
T1  - Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene
IS  - 1
VL  - 91
DO  - 10.1093/toxsci/kfj127
SP  - 173
EP  - 183
ER  - 

@article{
author = "Isaković, Aleksandra and Marković, Zoran and Todorović-Marković, Biljana and Nikolić, Nadežda and Vranješ-Đurić, Sanja and Mirković, Marija and Dramićanin, Miroslav and Harhaji-Trajković, Ljubica and Zogović, Nevena and Nikolić, Zoran and Trajković, Vladimir",
year = "2006",
abstract = "The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C 60 ) and water-soluble polyhydroxylated fullerene [C 60 (OH) n ] were investigated. Crystal violet assay for cell viability demonstrated that nano-C 60 was at least three orders of magnitude more toxic than C 60 (OH) n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C 60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C 60 (OH) n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C 60 toxicity, but not C 60 (OH) n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C 60 (OH) n -induced apoptosis, but not nano-C 60 -mediated necrosis. Finally, C 60 (OH) n antagomozed, while nano-C 60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C 60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C 60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.",
publisher = "Oxford University Press (OUP)",
journal = "Toxicological Sciences",
title = "Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene",
number = "1",
volume = "91",
doi = "10.1093/toxsci/kfj127",
pages = "173-183"
}

Isaković, A., Marković, Z., Todorović-Marković, B., Nikolić, N., Vranješ-Đurić, S., Mirković, M., Dramićanin, M., Harhaji-Trajković, L., Zogović, N., Nikolić, Z.,& Trajković, V.. (2006). Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene. in Toxicological Sciences
Oxford University Press (OUP)., 91(1), 173-183.
https://doi.org/10.1093/toxsci/kfj127

Isaković A, Marković Z, Todorović-Marković B, Nikolić N, Vranješ-Đurić S, Mirković M, Dramićanin M, Harhaji-Trajković L, Zogović N, Nikolić Z, Trajković V. Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene. in Toxicological Sciences. 2006;91(1):173-183.
doi:10.1093/toxsci/kfj127 .

Isaković, Aleksandra, Marković, Zoran, Todorović-Marković, Biljana, Nikolić, Nadežda, Vranješ-Đurić, Sanja, Mirković, Marija, Dramićanin, Miroslav, Harhaji-Trajković, Ljubica, Zogović, Nevena, Nikolić, Zoran, Trajković, Vladimir, "Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene" in Toxicological Sciences, 91, no. 1 (2006):173-183,
https://doi.org/10.1093/toxsci/kfj127 . .