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  - Zogovic, Nevena S.
AU  - Nikolić, Nadežda S.
AU  - Vranješ-Đurić, Sanja
AU  - Harhaji, Ljubica M.
AU  - Vucicevic, Ljubica M.
AU  - Janjetović, Kristina D.
AU  - Misirkić, Maja S.
AU  - Todorović-Marković, Biljana
AU  - Marković, Zoran M.
AU  - Milonjić, Slobodan K.
AU  - Trajković, Vladimir S.
PY  - 2009
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/3830
AB  - In the present study, we compared the effects of nanocrystalline fullerene suspension (nanoC(60)) on tumour cell growth in vitro and in vivo. NanoC(60) suspension was prepared by solvent exchange using tetrahydrofuran to dissolve C-60. In vitro, nanoC(60) caused oxidative stress, mitochondrial depolarization and caspase activation, leading to apoptotic and necrotic death in mouse B16 melanoma cells. Bio-distribution studies demonstrated that intraperitoneally injected radiolabeled (I-125) nanoC(60) readily accumulated in the tumour tissue of mice subcutaneously inoculated with B16 cells. However, intraperitoneal administration of nanoC(60) over the course of two weeks starting from melanoma cell implantation not only failed to reduce, but significantly augmented turnout growth. The tumour-promoting effect of nanoC(60) was accompanied by a significant increase in splenocyte production of the immunoregulatory free radical nitric oxide (NO), as well as by a reduction in splenocyte proliferative responses to T- and B-cell mitogens ConcanavalinA and bacterial lipopolysaccharide, respectively. A negative correlation between NO production and splenocyte proliferation indicated a possible role of NO in reducing the proliferation of splenocytes from nanoC(60)-injected mice. These data demonstrate that nanoC(60), in contrast to its potent anticancer activity in vitro, can potentiate tumour growth in vivo, possibly by causing NO-dependent suppression of anticancer immune response. (C) 2009 Elsevier Ltd. All rights reserved.
T2  - Biomaterials
T1  - Opposite effects of nanocrystalline fullerene (C-60) on tumour cell growth in vitro and in vivo and a possible role of immunosupression in the cancer-promoting activity of C-60
VL  - 30
IS  - 36
SP  - 6940
EP  - 6946
DO  - 10.1016/j.biomaterials.2009.09.007
ER  - 

@article{
author = "Zogovic, Nevena S. and Nikolić, Nadežda S. and Vranješ-Đurić, Sanja and Harhaji, Ljubica M. and Vucicevic, Ljubica M. and Janjetović, Kristina D. and Misirkić, Maja S. and Todorović-Marković, Biljana and Marković, Zoran M. and Milonjić, Slobodan K. and Trajković, Vladimir S.",
year = "2009",
abstract = "In the present study, we compared the effects of nanocrystalline fullerene suspension (nanoC(60)) on tumour cell growth in vitro and in vivo. NanoC(60) suspension was prepared by solvent exchange using tetrahydrofuran to dissolve C-60. In vitro, nanoC(60) caused oxidative stress, mitochondrial depolarization and caspase activation, leading to apoptotic and necrotic death in mouse B16 melanoma cells. Bio-distribution studies demonstrated that intraperitoneally injected radiolabeled (I-125) nanoC(60) readily accumulated in the tumour tissue of mice subcutaneously inoculated with B16 cells. However, intraperitoneal administration of nanoC(60) over the course of two weeks starting from melanoma cell implantation not only failed to reduce, but significantly augmented turnout growth. The tumour-promoting effect of nanoC(60) was accompanied by a significant increase in splenocyte production of the immunoregulatory free radical nitric oxide (NO), as well as by a reduction in splenocyte proliferative responses to T- and B-cell mitogens ConcanavalinA and bacterial lipopolysaccharide, respectively. A negative correlation between NO production and splenocyte proliferation indicated a possible role of NO in reducing the proliferation of splenocytes from nanoC(60)-injected mice. These data demonstrate that nanoC(60), in contrast to its potent anticancer activity in vitro, can potentiate tumour growth in vivo, possibly by causing NO-dependent suppression of anticancer immune response. (C) 2009 Elsevier Ltd. All rights reserved.",
journal = "Biomaterials",
title = "Opposite effects of nanocrystalline fullerene (C-60) on tumour cell growth in vitro and in vivo and a possible role of immunosupression in the cancer-promoting activity of C-60",
volume = "30",
number = "36",
pages = "6940-6946",
doi = "10.1016/j.biomaterials.2009.09.007"
}

Zogovic, N. S., Nikolić, N. S., Vranješ-Đurić, S., Harhaji, L. M., Vucicevic, L. M., Janjetović, K. D., Misirkić, M. S., Todorović-Marković, B., Marković, Z. M., Milonjić, S. K.,& Trajković, V. S.. (2009). Opposite effects of nanocrystalline fullerene (C-60) on tumour cell growth in vitro and in vivo and a possible role of immunosupression in the cancer-promoting activity of C-60. in Biomaterials, 30(36), 6940-6946.
https://doi.org/10.1016/j.biomaterials.2009.09.007

Zogovic NS, Nikolić NS, Vranješ-Đurić S, Harhaji LM, Vucicevic LM, Janjetović KD, Misirkić MS, Todorović-Marković B, Marković ZM, Milonjić SK, Trajković VS. Opposite effects of nanocrystalline fullerene (C-60) on tumour cell growth in vitro and in vivo and a possible role of immunosupression in the cancer-promoting activity of C-60. in Biomaterials. 2009;30(36):6940-6946.
doi:10.1016/j.biomaterials.2009.09.007 .

Zogovic, Nevena S., Nikolić, Nadežda S., Vranješ-Đurić, Sanja, Harhaji, Ljubica M., Vucicevic, Ljubica M., Janjetović, Kristina D., Misirkić, Maja S., Todorović-Marković, Biljana, Marković, Zoran M., Milonjić, Slobodan K., Trajković, Vladimir S., "Opposite effects of nanocrystalline fullerene (C-60) on tumour cell growth in vitro and in vivo and a possible role of immunosupression in the cancer-promoting activity of C-60" in Biomaterials, 30, no. 36 (2009):6940-6946,
https://doi.org/10.1016/j.biomaterials.2009.09.007 . .