TY  - JOUR
AU  - Tošić, Jelena
AU  - Stanojević, Željka
AU  - Vidičević, Sašenka
AU  - Isaković, Aleksandra J.
AU  - Ćirić, Darko
AU  - Martinović, Tamara
AU  - Kravić-Stevović, Tamara K.
AU  - Bumbaširević, Vladimir Ž.
AU  - Paunović, Verica G.
AU  - Jovanović, Svetlana P.
AU  - Todorović-Marković, Biljana
AU  - Marković, Zoran M.
AU  - Danko, Martin
AU  - Mičušik, Matej
AU  - Spitalsky, Zdenko
AU  - Trajković, Vladimir S.
PY  - 2019
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0028390818308621
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8015
AB  - We investigated the therapeutic capacity of nano-sized graphene sheets, called graphene quantum dots (GQD), in experimental autoimmune encephalomyelitis (EAE), an animal model of immune-mediated central nervous system (CNS) damage. Intraperitoneally administered GQD (10 mg/kg/day) accumulated in the lymph node and CNS cells of Dark Agouti rats in which EAE was induced by immunization with spinal cord homogenate in complete Freund's adjuvant. GQD significantly reduced clinical signs of EAE when applied throughout the course of the disease (day 0–32), while the protection was less pronounced if the treatment was limited to the induction (day 0–7 post-immunization) or effector (from day 8 onwards) phase of the disease. GQD treatment diminished immune infiltration, demyelination, axonal damage, and apoptotic death in the CNS of EAE animals. GQD also reduced the numbers of interferon-γ-expressing T helper (Th)1 cells, as well as the expression of Th1 transcription factor T-bet and proinflammatory cytokines tumor necrosis factor, interleukin-1, and granulocyte-macrophage colony-stimulating factor in the lymph nodes and CNS immune infitrates. The protective effect of GQD in EAE was associated with the activation of p38 and p42/44 mitogen-activated protein kinases (MAPK) and Akt in the lymph nodes and/or CNS. Finally, GQD protected oligodendrocytes and neurons from T cell-mediated damage in the in vitro conditions. Collectively, these data demonstrate the ability of GQD to gain access to both immune and CNS cells during neuroinflammation, and to alleviate immune-mediated CNS damage by modulating MAPK/Akt signaling and encephalitogenic Th1 immune response. © 2018 Elsevier Ltd
T2  - Neuropharmacology
T1  - Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats
VL  - 146
SP  - 95
EP  - 108
DO  - 10.1016/j.neuropharm.2018.11.030
ER  - 

@article{
author = "Tošić, Jelena and Stanojević, Željka and Vidičević, Sašenka and Isaković, Aleksandra J. and Ćirić, Darko and Martinović, Tamara and Kravić-Stevović, Tamara K. and Bumbaširević, Vladimir Ž. and Paunović, Verica G. and Jovanović, Svetlana P. and Todorović-Marković, Biljana and Marković, Zoran M. and Danko, Martin and Mičušik, Matej and Spitalsky, Zdenko and Trajković, Vladimir S.",
year = "2019",
abstract = "We investigated the therapeutic capacity of nano-sized graphene sheets, called graphene quantum dots (GQD), in experimental autoimmune encephalomyelitis (EAE), an animal model of immune-mediated central nervous system (CNS) damage. Intraperitoneally administered GQD (10 mg/kg/day) accumulated in the lymph node and CNS cells of Dark Agouti rats in which EAE was induced by immunization with spinal cord homogenate in complete Freund's adjuvant. GQD significantly reduced clinical signs of EAE when applied throughout the course of the disease (day 0–32), while the protection was less pronounced if the treatment was limited to the induction (day 0–7 post-immunization) or effector (from day 8 onwards) phase of the disease. GQD treatment diminished immune infiltration, demyelination, axonal damage, and apoptotic death in the CNS of EAE animals. GQD also reduced the numbers of interferon-γ-expressing T helper (Th)1 cells, as well as the expression of Th1 transcription factor T-bet and proinflammatory cytokines tumor necrosis factor, interleukin-1, and granulocyte-macrophage colony-stimulating factor in the lymph nodes and CNS immune infitrates. The protective effect of GQD in EAE was associated with the activation of p38 and p42/44 mitogen-activated protein kinases (MAPK) and Akt in the lymph nodes and/or CNS. Finally, GQD protected oligodendrocytes and neurons from T cell-mediated damage in the in vitro conditions. Collectively, these data demonstrate the ability of GQD to gain access to both immune and CNS cells during neuroinflammation, and to alleviate immune-mediated CNS damage by modulating MAPK/Akt signaling and encephalitogenic Th1 immune response. © 2018 Elsevier Ltd",
journal = "Neuropharmacology",
title = "Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats",
volume = "146",
pages = "95-108",
doi = "10.1016/j.neuropharm.2018.11.030"
}

Tošić, J., Stanojević, Ž., Vidičević, S., Isaković, A. J., Ćirić, D., Martinović, T., Kravić-Stevović, T. K., Bumbaširević, V. Ž., Paunović, V. G., Jovanović, S. P., Todorović-Marković, B., Marković, Z. M., Danko, M., Mičušik, M., Spitalsky, Z.,& Trajković, V. S.. (2019). Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats. in Neuropharmacology, 146, 95-108.
https://doi.org/10.1016/j.neuropharm.2018.11.030

Tošić J, Stanojević Ž, Vidičević S, Isaković AJ, Ćirić D, Martinović T, Kravić-Stevović TK, Bumbaširević VŽ, Paunović VG, Jovanović SP, Todorović-Marković B, Marković ZM, Danko M, Mičušik M, Spitalsky Z, Trajković VS. Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats. in Neuropharmacology. 2019;146:95-108.
doi:10.1016/j.neuropharm.2018.11.030 .

Tošić, Jelena, Stanojević, Željka, Vidičević, Sašenka, Isaković, Aleksandra J., Ćirić, Darko, Martinović, Tamara, Kravić-Stevović, Tamara K., Bumbaširević, Vladimir Ž., Paunović, Verica G., Jovanović, Svetlana P., Todorović-Marković, Biljana, Marković, Zoran M., Danko, Martin, Mičušik, Matej, Spitalsky, Zdenko, Trajković, Vladimir S., "Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats" in Neuropharmacology, 146 (2019):95-108,
https://doi.org/10.1016/j.neuropharm.2018.11.030 . .

TY  - CONF
AU  - Ćirić, Darko
AU  - Martinović, Tamara
AU  - Kravić-Stevović, Tamara K.
AU  - Volarević, Vladislav
AU  - Paunović, Verica G.
AU  - Marković, Zoran M.
AU  - Marković-Simović, Bojana
AU  - Misirkić-Marjanović, Maja
AU  - Todorović-Marković, Biljana
AU  - Bojić, Sanja
AU  - Vučićević, Ljubica
AU  - Jovanović, Svetlana P.
AU  - Arsenijević, Nebojša N.
AU  - Holclajtner-Antunović, Ivanka D.
AU  - Milosavljević, Momir
AU  - Dramićanin, Miroslav
AU  - Lukić, Miodrag L.
AU  - Trajković, Vladimir S.
AU  - Bumbaširević, Vladimir Ž.
PY  - 2018
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8741
PB  - Belgrade : Serbian Academy of Sciences and Arts
C3  - Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia
T1  - Ultrastructural Analysis of Large Graphene Quantum Dots Internalization in Hepatocytes
SP  - 272
EP  - 274
UR  - https://hdl.handle.net/21.15107/rcub_vinar_8741
ER  - 

@conference{
author = "Ćirić, Darko and Martinović, Tamara and Kravić-Stevović, Tamara K. and Volarević, Vladislav and Paunović, Verica G. and Marković, Zoran M. and Marković-Simović, Bojana and Misirkić-Marjanović, Maja and Todorović-Marković, Biljana and Bojić, Sanja and Vučićević, Ljubica and Jovanović, Svetlana P. and Arsenijević, Nebojša N. and Holclajtner-Antunović, Ivanka D. and Milosavljević, Momir and Dramićanin, Miroslav and Lukić, Miodrag L. and Trajković, Vladimir S. and Bumbaširević, Vladimir Ž.",
year = "2018",
publisher = "Belgrade : Serbian Academy of Sciences and Arts",
journal = "Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia",
title = "Ultrastructural Analysis of Large Graphene Quantum Dots Internalization in Hepatocytes",
pages = "272-274",
url = "https://hdl.handle.net/21.15107/rcub_vinar_8741"
}

Ćirić, D., Martinović, T., Kravić-Stevović, T. K., Volarević, V., Paunović, V. G., Marković, Z. M., Marković-Simović, B., Misirkić-Marjanović, M., Todorović-Marković, B., Bojić, S., Vučićević, L., Jovanović, S. P., Arsenijević, N. N., Holclajtner-Antunović, I. D., Milosavljević, M., Dramićanin, M., Lukić, M. L., Trajković, V. S.,& Bumbaširević, V. Ž.. (2018). Ultrastructural Analysis of Large Graphene Quantum Dots Internalization in Hepatocytes. in Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia
Belgrade : Serbian Academy of Sciences and Arts., 272-274.
https://hdl.handle.net/21.15107/rcub_vinar_8741

Ćirić D, Martinović T, Kravić-Stevović TK, Volarević V, Paunović VG, Marković ZM, Marković-Simović B, Misirkić-Marjanović M, Todorović-Marković B, Bojić S, Vučićević L, Jovanović SP, Arsenijević NN, Holclajtner-Antunović ID, Milosavljević M, Dramićanin M, Lukić ML, Trajković VS, Bumbaširević VŽ. Ultrastructural Analysis of Large Graphene Quantum Dots Internalization in Hepatocytes. in Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia. 2018;:272-274.
https://hdl.handle.net/21.15107/rcub_vinar_8741 .

Ćirić, Darko, Martinović, Tamara, Kravić-Stevović, Tamara K., Volarević, Vladislav, Paunović, Verica G., Marković, Zoran M., Marković-Simović, Bojana, Misirkić-Marjanović, Maja, Todorović-Marković, Biljana, Bojić, Sanja, Vučićević, Ljubica, Jovanović, Svetlana P., Arsenijević, Nebojša N., Holclajtner-Antunović, Ivanka D., Milosavljević, Momir, Dramićanin, Miroslav, Lukić, Miodrag L., Trajković, Vladimir S., Bumbaširević, Vladimir Ž., "Ultrastructural Analysis of Large Graphene Quantum Dots Internalization in Hepatocytes" in Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia (2018):272-274,
https://hdl.handle.net/21.15107/rcub_vinar_8741 .

TY  - CONF
AU  - Kravić-Stevović, Tamara K.
AU  - Martinović, Tamara
AU  - Ćirić, Darko
AU  - Paunović, Verica G.
AU  - Ristić, Biljana
AU  - Marković, Zoran M.
AU  - Todorović-Marković, Biljana
AU  - Kosić, Milica
AU  - Prekodravac, Jovana
AU  - Micusik, Matej
AU  - Spitalsky, Zdeno
AU  - Trajković, Vladimir S.
AU  - Harhaji-Trajković, Ljubica M.
AU  - Bumbaširević, Vladimir Ž.
PY  - 2018
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8740
PB  - Belgrade : Serbian Academy of Sciences and Arts
C3  - Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia
T1  - Transmission Electron Microscopy in Evaluation of Curcumin Nanoparticles Cellular Uptake
SP  - 266
EP  - 268
UR  - https://hdl.handle.net/21.15107/rcub_vinar_8740
ER  - 

@conference{
author = "Kravić-Stevović, Tamara K. and Martinović, Tamara and Ćirić, Darko and Paunović, Verica G. and Ristić, Biljana and Marković, Zoran M. and Todorović-Marković, Biljana and Kosić, Milica and Prekodravac, Jovana and Micusik, Matej and Spitalsky, Zdeno and Trajković, Vladimir S. and Harhaji-Trajković, Ljubica M. and Bumbaširević, Vladimir Ž.",
year = "2018",
publisher = "Belgrade : Serbian Academy of Sciences and Arts",
journal = "Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia",
title = "Transmission Electron Microscopy in Evaluation of Curcumin Nanoparticles Cellular Uptake",
pages = "266-268",
url = "https://hdl.handle.net/21.15107/rcub_vinar_8740"
}

Kravić-Stevović, T. K., Martinović, T., Ćirić, D., Paunović, V. G., Ristić, B., Marković, Z. M., Todorović-Marković, B., Kosić, M., Prekodravac, J., Micusik, M., Spitalsky, Z., Trajković, V. S., Harhaji-Trajković, L. M.,& Bumbaširević, V. Ž.. (2018). Transmission Electron Microscopy in Evaluation of Curcumin Nanoparticles Cellular Uptake. in Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia
Belgrade : Serbian Academy of Sciences and Arts., 266-268.
https://hdl.handle.net/21.15107/rcub_vinar_8740

Kravić-Stevović TK, Martinović T, Ćirić D, Paunović VG, Ristić B, Marković ZM, Todorović-Marković B, Kosić M, Prekodravac J, Micusik M, Spitalsky Z, Trajković VS, Harhaji-Trajković LM, Bumbaširević VŽ. Transmission Electron Microscopy in Evaluation of Curcumin Nanoparticles Cellular Uptake. in Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia. 2018;:266-268.
https://hdl.handle.net/21.15107/rcub_vinar_8740 .

Kravić-Stevović, Tamara K., Martinović, Tamara, Ćirić, Darko, Paunović, Verica G., Ristić, Biljana, Marković, Zoran M., Todorović-Marković, Biljana, Kosić, Milica, Prekodravac, Jovana, Micusik, Matej, Spitalsky, Zdeno, Trajković, Vladimir S., Harhaji-Trajković, Ljubica M., Bumbaširević, Vladimir Ž., "Transmission Electron Microscopy in Evaluation of Curcumin Nanoparticles Cellular Uptake" in Program and Book of Abstracts / First International Conference on Electron Microscopy of Nanostructures ELMINA 2018, August 27-29, 2018, Belgrade, Serbia (2018):266-268,
https://hdl.handle.net/21.15107/rcub_vinar_8740 .

TY  - JOUR
AU  - Marković, Zoran M.
AU  - Ristić, Biljana Z.
AU  - Arsikin, Katarina M.
AU  - Klisic, Djordje G.
AU  - Harhaji-Trajković, Ljubica M.
AU  - Todorović-Marković, Biljana
AU  - Kepić, Dejan P.
AU  - Kravić-Stevović, Tamara K.
AU  - Jovanović, Svetlana P.
AU  - Milenković, Marina
AU  - Milivojević, Dušan
AU  - Bumbaširević, Vladimir Ž.
AU  - Dramićanin, Miroslav
AU  - Trajković, Vladimir S.
PY  - 2012
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/5025
AB  - The excellent photoluminescent properties of graphene quantum dots (GQD) makes them suitable candidates for biomedical applications, but their cytotoxicity has not been extensively studied. Here we show that electrochemically produced GQD irradiated with blue light (470 nm, 1 W) generate reactive oxygen species, including singlet oxygen, and kill U251 human glioma cells by causing oxidative stress. The cell death induced by photoexcited GQD displayed morphological and/or biochemical characteristics of both apoptosis (phosphatidylserine externalization, caspase activation. DNA fragmentation) and autophagy (formation of autophagic vesicles, LC3-I/LC3-II conversion, degradation of autophagic target p62). Moreover, a genetic inactivation of autophagy-essential LOB protein partly abrogated the photodynamic cytotoxicity of GQD. These data indicate potential usefulness of GQD in photodynamic therapy, but also raise concerns about their possible toxicity. (C) 2012 Elsevier Ltd. All rights reserved.
T2  - Biomaterials
T1  - Graphene quantum dots as autophagy-inducing photodynamic agents
VL  - 33
IS  - 29
SP  - 7084
EP  - 7092
DO  - 10.1016/j.biomaterials.2012.06.060
ER  - 

@article{
author = "Marković, Zoran M. and Ristić, Biljana Z. and Arsikin, Katarina M. and Klisic, Djordje G. and Harhaji-Trajković, Ljubica M. and Todorović-Marković, Biljana and Kepić, Dejan P. and Kravić-Stevović, Tamara K. and Jovanović, Svetlana P. and Milenković, Marina and Milivojević, Dušan and Bumbaširević, Vladimir Ž. and Dramićanin, Miroslav and Trajković, Vladimir S.",
year = "2012",
abstract = "The excellent photoluminescent properties of graphene quantum dots (GQD) makes them suitable candidates for biomedical applications, but their cytotoxicity has not been extensively studied. Here we show that electrochemically produced GQD irradiated with blue light (470 nm, 1 W) generate reactive oxygen species, including singlet oxygen, and kill U251 human glioma cells by causing oxidative stress. The cell death induced by photoexcited GQD displayed morphological and/or biochemical characteristics of both apoptosis (phosphatidylserine externalization, caspase activation. DNA fragmentation) and autophagy (formation of autophagic vesicles, LC3-I/LC3-II conversion, degradation of autophagic target p62). Moreover, a genetic inactivation of autophagy-essential LOB protein partly abrogated the photodynamic cytotoxicity of GQD. These data indicate potential usefulness of GQD in photodynamic therapy, but also raise concerns about their possible toxicity. (C) 2012 Elsevier Ltd. All rights reserved.",
journal = "Biomaterials",
title = "Graphene quantum dots as autophagy-inducing photodynamic agents",
volume = "33",
number = "29",
pages = "7084-7092",
doi = "10.1016/j.biomaterials.2012.06.060"
}

Marković, Z. M., Ristić, B. Z., Arsikin, K. M., Klisic, D. G., Harhaji-Trajković, L. M., Todorović-Marković, B., Kepić, D. P., Kravić-Stevović, T. K., Jovanović, S. P., Milenković, M., Milivojević, D., Bumbaširević, V. Ž., Dramićanin, M.,& Trajković, V. S.. (2012). Graphene quantum dots as autophagy-inducing photodynamic agents. in Biomaterials, 33(29), 7084-7092.
https://doi.org/10.1016/j.biomaterials.2012.06.060

Marković ZM, Ristić BZ, Arsikin KM, Klisic DG, Harhaji-Trajković LM, Todorović-Marković B, Kepić DP, Kravić-Stevović TK, Jovanović SP, Milenković M, Milivojević D, Bumbaširević VŽ, Dramićanin M, Trajković VS. Graphene quantum dots as autophagy-inducing photodynamic agents. in Biomaterials. 2012;33(29):7084-7092.
doi:10.1016/j.biomaterials.2012.06.060 .

Marković, Zoran M., Ristić, Biljana Z., Arsikin, Katarina M., Klisic, Djordje G., Harhaji-Trajković, Ljubica M., Todorović-Marković, Biljana, Kepić, Dejan P., Kravić-Stevović, Tamara K., Jovanović, Svetlana P., Milenković, Marina, Milivojević, Dušan, Bumbaširević, Vladimir Ž., Dramićanin, Miroslav, Trajković, Vladimir S., "Graphene quantum dots as autophagy-inducing photodynamic agents" in Biomaterials, 33, no. 29 (2012):7084-7092,
https://doi.org/10.1016/j.biomaterials.2012.06.060 . .

TY  - JOUR
AU  - Janjetović, Kristina D.
AU  - Vucicevic, Ljubica
AU  - Misirkić, Maja
AU  - Vilimanovich, Urosh
AU  - Tovilovic, Gordana
AU  - Zogovic, Nevena
AU  - Nikolić, Zoran M.
AU  - Jovanović, Svetlana P.
AU  - Bumbaširević, Vladimir Ž.
AU  - Trajković, Vladimir S.
AU  - Harhaji-Trajković, Ljubica M.
PY  - 2011
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/4205
AB  - Metformin is an antidiabetic drug with anticancer properties, which mainly acts through induction of AMP-activated protein kinase (AMPK). In the present study we investigated the influence of metformin on the in vitro anticancer activity of the well-known chemotherapeutic agent cisplatin. Cell viability was determined by MTT and LDH release assay, oxidative stress and apoptosis (caspase activation, DNA fragmentation, and phosphatidylserine exposure) were assessed by flow cytometry, while activation of AMPK and Akt was analyzed by immunoblotting. Although metformin reduced the number of tumour cells when applied alone, it surprisingly antagonized the cytotoxicity of cisplatin towards U251 human glioma, C6 rat glioma, SHSY5Y human neuroblastoma, L929 mouse fibrosarcoma and HL-60 human leukemia cell lines. Only in B16 mouse melanoma cells metformin augmented the cytotoxicity of cisplatin. In U251 glioma cells metformin suppressed cisplatin-induced apoptotic cell death through inhibition of oxidative stress and caspase activation. The observed cytoprotection was apparently AMPK-independent, as metformin did not further increase cisplatin-induced AMPK activation in U251 cells and other pharmacological AMPK activators failed to block cisplatin-mediated apoptosis. On the other hand, metformin induced Akt activation in cisplatin-treated cells and Akt inhibitor 10-DEBC hydrochloride or phosphoinositide 3-kinase/Akt inhibitor LY294002 abolished metformin-mediated antioxidant and antiapoptotic effects. In conclusion, the antidiabetic drug metformin reduces cisplatin in vitro anticancer activity through AMPK-independent upregulation of Akt survival pathway. These data warrant caution when considering metformin for treatment of diabetic cancer patients receiving cisplatin or as a potential adjuvant in cisplatin-based chemotherapeutic regimens. (c) 2010 Published by Elsevier B.V.
T2  - European Journal of Pharmacology
T1  - Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt
VL  - 651
IS  - 1-3
SP  - 41
EP  - 50
DO  - 10.1016/j.ejphar.2010.11.005
ER  - 

@article{
author = "Janjetović, Kristina D. and Vucicevic, Ljubica and Misirkić, Maja and Vilimanovich, Urosh and Tovilovic, Gordana and Zogovic, Nevena and Nikolić, Zoran M. and Jovanović, Svetlana P. and Bumbaširević, Vladimir Ž. and Trajković, Vladimir S. and Harhaji-Trajković, Ljubica M.",
year = "2011",
abstract = "Metformin is an antidiabetic drug with anticancer properties, which mainly acts through induction of AMP-activated protein kinase (AMPK). In the present study we investigated the influence of metformin on the in vitro anticancer activity of the well-known chemotherapeutic agent cisplatin. Cell viability was determined by MTT and LDH release assay, oxidative stress and apoptosis (caspase activation, DNA fragmentation, and phosphatidylserine exposure) were assessed by flow cytometry, while activation of AMPK and Akt was analyzed by immunoblotting. Although metformin reduced the number of tumour cells when applied alone, it surprisingly antagonized the cytotoxicity of cisplatin towards U251 human glioma, C6 rat glioma, SHSY5Y human neuroblastoma, L929 mouse fibrosarcoma and HL-60 human leukemia cell lines. Only in B16 mouse melanoma cells metformin augmented the cytotoxicity of cisplatin. In U251 glioma cells metformin suppressed cisplatin-induced apoptotic cell death through inhibition of oxidative stress and caspase activation. The observed cytoprotection was apparently AMPK-independent, as metformin did not further increase cisplatin-induced AMPK activation in U251 cells and other pharmacological AMPK activators failed to block cisplatin-mediated apoptosis. On the other hand, metformin induced Akt activation in cisplatin-treated cells and Akt inhibitor 10-DEBC hydrochloride or phosphoinositide 3-kinase/Akt inhibitor LY294002 abolished metformin-mediated antioxidant and antiapoptotic effects. In conclusion, the antidiabetic drug metformin reduces cisplatin in vitro anticancer activity through AMPK-independent upregulation of Akt survival pathway. These data warrant caution when considering metformin for treatment of diabetic cancer patients receiving cisplatin or as a potential adjuvant in cisplatin-based chemotherapeutic regimens. (c) 2010 Published by Elsevier B.V.",
journal = "European Journal of Pharmacology",
title = "Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt",
volume = "651",
number = "1-3",
pages = "41-50",
doi = "10.1016/j.ejphar.2010.11.005"
}

Janjetović, K. D., Vucicevic, L., Misirkić, M., Vilimanovich, U., Tovilovic, G., Zogovic, N., Nikolić, Z. M., Jovanović, S. P., Bumbaširević, V. Ž., Trajković, V. S.,& Harhaji-Trajković, L. M.. (2011). Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. in European Journal of Pharmacology, 651(1-3), 41-50.
https://doi.org/10.1016/j.ejphar.2010.11.005

Janjetović KD, Vucicevic L, Misirkić M, Vilimanovich U, Tovilovic G, Zogovic N, Nikolić ZM, Jovanović SP, Bumbaširević VŽ, Trajković VS, Harhaji-Trajković LM. Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. in European Journal of Pharmacology. 2011;651(1-3):41-50.
doi:10.1016/j.ejphar.2010.11.005 .

Janjetović, Kristina D., Vucicevic, Ljubica, Misirkić, Maja, Vilimanovich, Urosh, Tovilovic, Gordana, Zogovic, Nevena, Nikolić, Zoran M., Jovanović, Svetlana P., Bumbaširević, Vladimir Ž., Trajković, Vladimir S., Harhaji-Trajković, Ljubica M., "Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt" in European Journal of Pharmacology, 651, no. 1-3 (2011):41-50,
https://doi.org/10.1016/j.ejphar.2010.11.005 . .

TY  - JOUR
AU  - Vucicevic, Ljubica
AU  - Misirkić, Maja
AU  - Janjetović, Kristina D.
AU  - Vilimanovich, Urosh
AU  - Sudar, Emina
AU  - Isenović, Esma R.
AU  - Prica, Marko
AU  - Harhaji-Trajković, Ljubica M.
AU  - Kravić-Stevović, Tamara K.
AU  - Bumbaširević, Vladimir Ž.
AU  - Trajković, Vladimir S.
PY  - 2011
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/4180
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
VL  - 7
IS  - 1
SP  - 40
EP  - 50
DO  - 10.4161/auto.7.1.13883
ER  - 

@article{
author = "Vucicevic, Ljubica and Misirkić, Maja and Janjetović, Kristina D. and Vilimanovich, Urosh and Sudar, Emina and Isenović, Esma R. and Prica, Marko and Harhaji-Trajković, Ljubica M. and Kravić-Stevović, Tamara K. and Bumbaširević, Vladimir Ž. 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",
volume = "7",
number = "1",
pages = "40-50",
doi = "10.4161/auto.7.1.13883"
}

Vucicevic, L., Misirkić, M., Janjetović, K. D., Vilimanovich, U., Sudar, E., Isenović, E. R., Prica, M., Harhaji-Trajković, L. M., Kravić-Stevović, T. K., Bumbaširević, V. Ž.,& 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), 40-50.
https://doi.org/10.4161/auto.7.1.13883

Vucicevic L, Misirkić M, Janjetović KD, Vilimanovich U, Sudar E, Isenović ER, Prica M, Harhaji-Trajković LM, Kravić-Stevović TK, Bumbaširević VŽ, Trajković VS. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. in Autophagy. 2011;7(1):40-50.
doi:10.4161/auto.7.1.13883 .

Vucicevic, Ljubica, Misirkić, Maja, Janjetović, Kristina D., Vilimanovich, Urosh, Sudar, Emina, Isenović, Esma R., Prica, Marko, Harhaji-Trajković, Ljubica M., Kravić-Stevović, Tamara K., Bumbaširević, Vladimir Ž., 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):40-50,
https://doi.org/10.4161/auto.7.1.13883 . .