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  - Harhaji-Trajković, Ljubica
AU  - Isaković, Aleksandra
AU  - Zogović, Nevena
AU  - Marković, Zoran
AU  - Todorović-Marković, Biljana
AU  - Nikolić, Nadežda
AU  - Vranješ-Đurić, Sanja
AU  - Marković, Ivanka
AU  - Trajković, Vladimir
PY  - 2007
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6544
AB  - Using the rat glioma cell line C6 and the human glioma cell line U251, we demonstrate the multiple mechanisms underlying the in vitro anticancer effects of the C(60) fullerene water suspension (nano-C(60) or nC(60)) produced by solvent exchange method. Nano-C(60) in a dose-dependent manner reduced the tumor cell numbers after 24 h of incubation. The observed antiglioma action of nC(60) at high concentration (1 microg/ml) was due to a reactive oxygen species-mediated necrotic cell damage that was partly dependent on oxidative stress-induced activation of extracellular signal-regulated kinase (ERK). On the other hand, low-dose nC(60) (0.25 microg/ml) did not induce either necrotic or apoptotic cell death, but caused oxidative stress/ERK-independent cell cycle block in G(2)/M phase and subsequent inhibition of tumor cell proliferation. Treatment with either high-dose or low-dose nC(60) caused the appearance of acidified intracytoplasmic vesicles indicative of autophagy, but only the antiglioma effect of low-dose nC(60) was significantly attenuated by inhibiting autophagy with bafilomycin A1. Importantly, primary rat astrocytes were less sensitive than their transformed counterparts to a cytostatic action of low-dose nC(60). These data provide grounds for further development of nC(60) as an anticancer agent.
PB  - Elsevier BV
T2  - European Journal of Pharmacology
T1  - Multiple mechanisms underlying the anticancer action of nanocrystalline fullerene
IS  - 1-3
VL  - 568
DO  - 10.1016/j.ejphar.2007.04.041
SP  - 89
EP  - 98
ER  - 

@article{
author = "Harhaji-Trajković, Ljubica and Isaković, Aleksandra and Zogović, Nevena and Marković, Zoran and Todorović-Marković, Biljana and Nikolić, Nadežda and Vranješ-Đurić, Sanja and Marković, Ivanka and Trajković, Vladimir",
year = "2007",
abstract = "Using the rat glioma cell line C6 and the human glioma cell line U251, we demonstrate the multiple mechanisms underlying the in vitro anticancer effects of the C(60) fullerene water suspension (nano-C(60) or nC(60)) produced by solvent exchange method. Nano-C(60) in a dose-dependent manner reduced the tumor cell numbers after 24 h of incubation. The observed antiglioma action of nC(60) at high concentration (1 microg/ml) was due to a reactive oxygen species-mediated necrotic cell damage that was partly dependent on oxidative stress-induced activation of extracellular signal-regulated kinase (ERK). On the other hand, low-dose nC(60) (0.25 microg/ml) did not induce either necrotic or apoptotic cell death, but caused oxidative stress/ERK-independent cell cycle block in G(2)/M phase and subsequent inhibition of tumor cell proliferation. Treatment with either high-dose or low-dose nC(60) caused the appearance of acidified intracytoplasmic vesicles indicative of autophagy, but only the antiglioma effect of low-dose nC(60) was significantly attenuated by inhibiting autophagy with bafilomycin A1. Importantly, primary rat astrocytes were less sensitive than their transformed counterparts to a cytostatic action of low-dose nC(60). These data provide grounds for further development of nC(60) as an anticancer agent.",
publisher = "Elsevier BV",
journal = "European Journal of Pharmacology",
title = "Multiple mechanisms underlying the anticancer action of nanocrystalline fullerene",
number = "1-3",
volume = "568",
doi = "10.1016/j.ejphar.2007.04.041",
pages = "89-98"
}

Harhaji-Trajković, L., Isaković, A., Zogović, N., Marković, Z., Todorović-Marković, B., Nikolić, N., Vranješ-Đurić, S., Marković, I.,& Trajković, V.. (2007). Multiple mechanisms underlying the anticancer action of nanocrystalline fullerene. in European Journal of Pharmacology
Elsevier BV., 568(1-3), 89-98.
https://doi.org/10.1016/j.ejphar.2007.04.041

Harhaji-Trajković L, Isaković A, Zogović N, Marković Z, Todorović-Marković B, Nikolić N, Vranješ-Đurić S, Marković I, Trajković V. Multiple mechanisms underlying the anticancer action of nanocrystalline fullerene. in European Journal of Pharmacology. 2007;568(1-3):89-98.
doi:10.1016/j.ejphar.2007.04.041 .

Harhaji-Trajković, Ljubica, Isaković, Aleksandra, Zogović, Nevena, Marković, Zoran, Todorović-Marković, Biljana, Nikolić, Nadežda, Vranješ-Đurić, Sanja, Marković, Ivanka, Trajković, Vladimir, "Multiple mechanisms underlying the anticancer action of nanocrystalline fullerene" in European Journal of Pharmacology, 568, no. 1-3 (2007):89-98,
https://doi.org/10.1016/j.ejphar.2007.04.041 . .