TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Stockmann, Philipp
AU  - Mijatović, Sanja
AU  - Kuhnert, Lydia
AU  - Honscha, Walther
AU  - Hey-Hawkins, Evamarie
AU  - Maksimović-Ivanić, Danijela
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6489
AB  - Abstract: The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug
resistance, has the ability to transport a broad spectrum of substrates out of the cell and is,
therefore, considered as a potential target to improve cancer therapies or as an approach to combat
drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives
as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein
(BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most
promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell
lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently,
with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy
of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic
effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa,
DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480
cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest
expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the
effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly,
co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic
effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However,
a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition
by the carborane derivatives emerges as a possible reason.
PB  - Basel: MDPI
T2  - Pharmaceuticals
T1  - Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin
IS  - 11
VL  - 16
DO  - 10.3390/ph16111582
SP  - 1582
ER  - 

@article{
author = "Paskaš, Svetlana and Stockmann, Philipp and Mijatović, Sanja and Kuhnert, Lydia and Honscha, Walther and Hey-Hawkins, Evamarie and Maksimović-Ivanić, Danijela",
year = "2023",
abstract = "Abstract: The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug
resistance, has the ability to transport a broad spectrum of substrates out of the cell and is,
therefore, considered as a potential target to improve cancer therapies or as an approach to combat
drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives
as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein
(BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most
promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell
lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently,
with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy
of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic
effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa,
DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480
cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest
expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the
effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly,
co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic
effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However,
a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition
by the carborane derivatives emerges as a possible reason.",
publisher = "Basel: MDPI",
journal = "Pharmaceuticals",
title = "Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin",
number = "11",
volume = "16",
doi = "10.3390/ph16111582",
pages = "1582"
}

Paskaš, S., Stockmann, P., Mijatović, S., Kuhnert, L., Honscha, W., Hey-Hawkins, E.,& Maksimović-Ivanić, D.. (2023). Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin. in Pharmaceuticals
Basel: MDPI., 16(11), 1582.
https://doi.org/10.3390/ph16111582

Paskaš S, Stockmann P, Mijatović S, Kuhnert L, Honscha W, Hey-Hawkins E, Maksimović-Ivanić D. Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin. in Pharmaceuticals. 2023;16(11):1582.
doi:10.3390/ph16111582 .

Paskaš, Svetlana, Stockmann, Philipp, Mijatović, Sanja, Kuhnert, Lydia, Honscha, Walther, Hey-Hawkins, Evamarie, Maksimović-Ivanić, Danijela, "Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin" in Pharmaceuticals, 16, no. 11 (2023):1582,
https://doi.org/10.3390/ph16111582 . .

TY  - JOUR
AU  - Braun, Sebastian
AU  - Paskaš, Svetlana
AU  - Laube, Markus
AU  - George, Sven
AU  - Hofmann, Bettina
AU  - Lönnecke, Peter
AU  - Steinhilber, Dieter
AU  - Pietzsch, Jens
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Hey-Hawkins, Evamarie
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6431
AB  - The presence of inflammatory mediators in the tumor microenvironment,
such as cytokines, growth factors or eicosanoids,
indicate cancer-related inflammatory processes. Targeting these
inflammatory mediators and related signal pathways may offer
a rational strategy for the treatment of cancer. This study
focuses on the incorporation of metabolically stable, sterically
demanding, and hydrophobic dicarba-closo-dodecaboranes
(carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase
(5-LO) inhibitors that are key enzymes in the biosynthesis
of eicosanoids. The di-tert-butylphenol derivative tebufelone
represents a selective dual COX-2/5-LO inhibitor. The incorporation
of meta- or para-carborane into the tebufelone scaffold
resulted in eight carborane-based tebufelone analogs that
show no COX inhibition but 5-LO inhibitory activity in vitro. Cell
viability studies on HT29 colon adenocarcinoma cells revealed
that the observed antiproliferative effect of the para-carborane
analogs of tebufelone is enhanced by structural modifications
that include chain elongation in combination with introduction
of a methylene spacer resulting in higher anticancer activity
compared to tebufelone. Hence, this strategy proved to be a
promising approach to design potent 5-LO inhibitors with
potential application as cytostatic agents.
PB  - Wiley-VCH GmbH
T2  - ChemMedChem
T1  - Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro
IS  - 14
VL  - 18
DO  - 10.1002/cmdc.202300206
SP  - e202300206
ER  - 

@article{
author = "Braun, Sebastian and Paskaš, Svetlana and Laube, Markus and George, Sven and Hofmann, Bettina and Lönnecke, Peter and Steinhilber, Dieter and Pietzsch, Jens and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Hey-Hawkins, Evamarie",
year = "2023",
abstract = "The presence of inflammatory mediators in the tumor microenvironment,
such as cytokines, growth factors or eicosanoids,
indicate cancer-related inflammatory processes. Targeting these
inflammatory mediators and related signal pathways may offer
a rational strategy for the treatment of cancer. This study
focuses on the incorporation of metabolically stable, sterically
demanding, and hydrophobic dicarba-closo-dodecaboranes
(carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase
(5-LO) inhibitors that are key enzymes in the biosynthesis
of eicosanoids. The di-tert-butylphenol derivative tebufelone
represents a selective dual COX-2/5-LO inhibitor. The incorporation
of meta- or para-carborane into the tebufelone scaffold
resulted in eight carborane-based tebufelone analogs that
show no COX inhibition but 5-LO inhibitory activity in vitro. Cell
viability studies on HT29 colon adenocarcinoma cells revealed
that the observed antiproliferative effect of the para-carborane
analogs of tebufelone is enhanced by structural modifications
that include chain elongation in combination with introduction
of a methylene spacer resulting in higher anticancer activity
compared to tebufelone. Hence, this strategy proved to be a
promising approach to design potent 5-LO inhibitors with
potential application as cytostatic agents.",
publisher = "Wiley-VCH GmbH",
journal = "ChemMedChem",
title = "Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro",
number = "14",
volume = "18",
doi = "10.1002/cmdc.202300206",
pages = "e202300206"
}

Braun, S., Paskaš, S., Laube, M., George, S., Hofmann, B., Lönnecke, P., Steinhilber, D., Pietzsch, J., Mijatović, S., Maksimović-Ivanić, D.,& Hey-Hawkins, E.. (2023). Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro. in ChemMedChem
Wiley-VCH GmbH., 18(14), e202300206.
https://doi.org/10.1002/cmdc.202300206

Braun S, Paskaš S, Laube M, George S, Hofmann B, Lönnecke P, Steinhilber D, Pietzsch J, Mijatović S, Maksimović-Ivanić D, Hey-Hawkins E. Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro. in ChemMedChem. 2023;18(14):e202300206.
doi:10.1002/cmdc.202300206 .

Braun, Sebastian, Paskaš, Svetlana, Laube, Markus, George, Sven, Hofmann, Bettina, Lönnecke, Peter, Steinhilber, Dieter, Pietzsch, Jens, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey-Hawkins, Evamarie, "Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro" in ChemMedChem, 18, no. 14 (2023):e202300206,
https://doi.org/10.1002/cmdc.202300206 . .

TY  - JOUR
AU  - Stockmann, Philipp
AU  - Kuhnert, Lydia
AU  - Leinung, Wencke
AU  - Lakoma, Cathleen
AU  - Scholz, Birte
AU  - Paskaš, Svetlana
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Honscha, Walther
AU  - Hey-Hawkins, Evamarie
PY  - 2023
UR  - https://www.mdpi.com/1999-4923/15/1/241
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC9866861
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5434
AB  - The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents' pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.
PB  - Basel: MDPI
T2  - Pharmaceutics
T1  - The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors
IS  - 1
VL  - 15
DO  - 10.3390/pharmaceutics15010241
SP  - 241
ER  - 

@article{
author = "Stockmann, Philipp and Kuhnert, Lydia and Leinung, Wencke and Lakoma, Cathleen and Scholz, Birte and Paskaš, Svetlana and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Honscha, Walther and Hey-Hawkins, Evamarie",
year = "2023",
abstract = "The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents' pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.",
publisher = "Basel: MDPI",
journal = "Pharmaceutics",
title = "The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors",
number = "1",
volume = "15",
doi = "10.3390/pharmaceutics15010241",
pages = "241"
}

Stockmann, P., Kuhnert, L., Leinung, W., Lakoma, C., Scholz, B., Paskaš, S., Mijatović, S., Maksimović-Ivanić, D., Honscha, W.,& Hey-Hawkins, E.. (2023). The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. in Pharmaceutics
Basel: MDPI., 15(1), 241.
https://doi.org/10.3390/pharmaceutics15010241

Stockmann P, Kuhnert L, Leinung W, Lakoma C, Scholz B, Paskaš S, Mijatović S, Maksimović-Ivanić D, Honscha W, Hey-Hawkins E. The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. in Pharmaceutics. 2023;15(1):241.
doi:10.3390/pharmaceutics15010241 .

Stockmann, Philipp, Kuhnert, Lydia, Leinung, Wencke, Lakoma, Cathleen, Scholz, Birte, Paskaš, Svetlana, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Honscha, Walther, Hey-Hawkins, Evamarie, "The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors" in Pharmaceutics, 15, no. 1 (2023):241,
https://doi.org/10.3390/pharmaceutics15010241 . .

TY  - JOUR
AU  - Braun, Sebastian
AU  - Paskaš, Svetlana
AU  - Laube, Markus
AU  - George, Sven
AU  - Hofmann, Bettina
AU  - Lönnecke, Peter
AU  - Steinhilber, Dieter
AU  - Pietzsch, Jens
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Hey‐Hawkins, Evamarie
PY  - 2023
UR  - https://onlinelibrary.wiley.com/doi/10.1002/adtp.202200252
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5384
AB  - The selective inhibition of enzymes that catalyze the conversion of arachidonic acid to inflammatory eicosanoids represents a promising approach for cancer therapy. This study, therefore, focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes into existing dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. Here, the first carborane-containing dual COX-2/5-LO inhibitors derived from RWJ-63556 are presented. The replacement of the fluorophenyl moiety by meta- or para-carborane resulted in five carborane-containing derivatives 3, 6, 9, 13, and 17 that show high inhibitory activities toward COX-2 and 5-LO in vitro. Cell viability studies on the A375 melanoma cell line revealed that meta-carborane derivative 3 shows higher anticancer activity compared to RWJ-63556 based on accumulation of lipid droplets in the cells due to blockage of the COX-2 and 5-LO pathways, indicating a promising approach for the design of potent dual COX-2/5-LO inhibitors.
T2  - Advanced Therapeutics
T1  - In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors
DO  - 10.1002/adtp.202200252
SP  - 2200252
ER  - 

@article{
author = "Braun, Sebastian and Paskaš, Svetlana and Laube, Markus and George, Sven and Hofmann, Bettina and Lönnecke, Peter and Steinhilber, Dieter and Pietzsch, Jens and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Hey‐Hawkins, Evamarie",
year = "2023",
abstract = "The selective inhibition of enzymes that catalyze the conversion of arachidonic acid to inflammatory eicosanoids represents a promising approach for cancer therapy. This study, therefore, focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes into existing dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. Here, the first carborane-containing dual COX-2/5-LO inhibitors derived from RWJ-63556 are presented. The replacement of the fluorophenyl moiety by meta- or para-carborane resulted in five carborane-containing derivatives 3, 6, 9, 13, and 17 that show high inhibitory activities toward COX-2 and 5-LO in vitro. Cell viability studies on the A375 melanoma cell line revealed that meta-carborane derivative 3 shows higher anticancer activity compared to RWJ-63556 based on accumulation of lipid droplets in the cells due to blockage of the COX-2 and 5-LO pathways, indicating a promising approach for the design of potent dual COX-2/5-LO inhibitors.",
journal = "Advanced Therapeutics",
title = "In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors",
doi = "10.1002/adtp.202200252",
pages = "2200252"
}

Braun, S., Paskaš, S., Laube, M., George, S., Hofmann, B., Lönnecke, P., Steinhilber, D., Pietzsch, J., Mijatović, S., Maksimović-Ivanić, D.,& Hey‐Hawkins, E.. (2023). In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors. in Advanced Therapeutics, 2200252.
https://doi.org/10.1002/adtp.202200252

Braun S, Paskaš S, Laube M, George S, Hofmann B, Lönnecke P, Steinhilber D, Pietzsch J, Mijatović S, Maksimović-Ivanić D, Hey‐Hawkins E. In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors. in Advanced Therapeutics. 2023;:2200252.
doi:10.1002/adtp.202200252 .

Braun, Sebastian, Paskaš, Svetlana, Laube, Markus, George, Sven, Hofmann, Bettina, Lönnecke, Peter, Steinhilber, Dieter, Pietzsch, Jens, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey‐Hawkins, Evamarie, "In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors" in Advanced Therapeutics (2023):2200252,
https://doi.org/10.1002/adtp.202200252 . .

TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Murganić, Blagoje
AU  - Kuhnert, Robert
AU  - Hey-Hawkins, Evamarie
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2022
UR  - https://www.mdpi.com/1420-3049/27/14/4503
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC9321230
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5088
AB  - Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC50 values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.
PB  - Basel: MDPI
T2  - Molecules (Basel, Switzerland)
T1  - Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.
IS  - 14
VL  - 27
DO  - 10.3390/molecules27144503
SP  - 4503
ER  - 

@article{
author = "Paskaš, Svetlana and Murganić, Blagoje and Kuhnert, Robert and Hey-Hawkins, Evamarie and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2022",
abstract = "Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC50 values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.",
publisher = "Basel: MDPI",
journal = "Molecules (Basel, Switzerland)",
title = "Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.",
number = "14",
volume = "27",
doi = "10.3390/molecules27144503",
pages = "4503"
}

Paskaš, S., Murganić, B., Kuhnert, R., Hey-Hawkins, E., Mijatović, S.,& Maksimović-Ivanić, D.. (2022). Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.. in Molecules (Basel, Switzerland)
Basel: MDPI., 27(14), 4503.
https://doi.org/10.3390/molecules27144503

Paskaš S, Murganić B, Kuhnert R, Hey-Hawkins E, Mijatović S, Maksimović-Ivanić D. Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo.. in Molecules (Basel, Switzerland). 2022;27(14):4503.
doi:10.3390/molecules27144503 .

Paskaš, Svetlana, Murganić, Blagoje, Kuhnert, Robert, Hey-Hawkins, Evamarie, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo." in Molecules (Basel, Switzerland), 27, no. 14 (2022):4503,
https://doi.org/10.3390/molecules27144503 . .

TY  - JOUR
AU  - Kuhnert, Robert
AU  - Kuhnert, Lydia
AU  - Sárosi, Menyhárt‐B.
AU  - George, Sven
AU  - Drača, Dijana
AU  - Paskaš, Svetlana
AU  - Hofmann, Bettina
AU  - Steinhilber, Dieter
AU  - Honscha, Walther
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Hey-Hawkins, Evamarie
PY  - 2022
UR  - https://onlinelibrary.wiley.com/doi/10.1002/cmdc.202100588
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4686
AB  - 12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO).
PB  - Weinheim: John Wiley and Sons Ltd.
T2  - ChemMedChem
T1  - Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity
IS  - 1
VL  - 17
DO  - 10.1002/cmdc.202100588
SP  - e202100588
ER  - 

@article{
author = "Kuhnert, Robert and Kuhnert, Lydia and Sárosi, Menyhárt‐B. and George, Sven and Drača, Dijana and Paskaš, Svetlana and Hofmann, Bettina and Steinhilber, Dieter and Honscha, Walther and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Hey-Hawkins, Evamarie",
year = "2022",
abstract = "12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO).",
publisher = "Weinheim: John Wiley and Sons Ltd.",
journal = "ChemMedChem",
title = "Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity",
number = "1",
volume = "17",
doi = "10.1002/cmdc.202100588",
pages = "e202100588"
}

Kuhnert, R., Kuhnert, L., Sárosi, Menyhárt‐B., George, S., Drača, D., Paskaš, S., Hofmann, B., Steinhilber, D., Honscha, W., Mijatović, S., Maksimović-Ivanić, D.,& Hey-Hawkins, E.. (2022). Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity. in ChemMedChem
Weinheim: John Wiley and Sons Ltd.., 17(1), e202100588.
https://doi.org/10.1002/cmdc.202100588

Kuhnert R, Kuhnert L, Sárosi M, George S, Drača D, Paskaš S, Hofmann B, Steinhilber D, Honscha W, Mijatović S, Maksimović-Ivanić D, Hey-Hawkins E. Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity. in ChemMedChem. 2022;17(1):e202100588.
doi:10.1002/cmdc.202100588 .

Kuhnert, Robert, Kuhnert, Lydia, Sárosi, Menyhárt‐B., George, Sven, Drača, Dijana, Paskaš, Svetlana, Hofmann, Bettina, Steinhilber, Dieter, Honscha, Walther, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey-Hawkins, Evamarie, "Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity" in ChemMedChem, 17, no. 1 (2022):e202100588,
https://doi.org/10.1002/cmdc.202100588 . .

TY  - JOUR
AU  - Buzharevski, Antonio
AU  - Paskaš, Svetlana
AU  - Sárosi, Menyhárt-Botond
AU  - Laube, Markus
AU  - Lönnecke, Peter
AU  - Neumann, Wilma
AU  - Murganić, Blagoje
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Pietzsch, Jens
AU  - Hey-Hawkins, Evamarie
PY  - 2020
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32179835
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC7076013
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3640
AB  - Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.
T2  - Scientific Reports
T1  - Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.
IS  - 1
VL  - 10
DO  - 10.1038/s41598-020-59059-3
SP  - 4827
ER  - 

@article{
author = "Buzharevski, Antonio and Paskaš, Svetlana and Sárosi, Menyhárt-Botond and Laube, Markus and Lönnecke, Peter and Neumann, Wilma and Murganić, Blagoje and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Pietzsch, Jens and Hey-Hawkins, Evamarie",
year = "2020",
abstract = "Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.",
journal = "Scientific Reports",
title = "Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.",
number = "1",
volume = "10",
doi = "10.1038/s41598-020-59059-3",
pages = "4827"
}

Buzharevski, A., Paskaš, S., Sárosi, M., Laube, M., Lönnecke, P., Neumann, W., Murganić, B., Mijatović, S., Maksimović-Ivanić, D., Pietzsch, J.,& Hey-Hawkins, E.. (2020). Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.. in Scientific Reports, 10(1), 4827.
https://doi.org/10.1038/s41598-020-59059-3

Buzharevski A, Paskaš S, Sárosi M, Laube M, Lönnecke P, Neumann W, Murganić B, Mijatović S, Maksimović-Ivanić D, Pietzsch J, Hey-Hawkins E. Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.. in Scientific Reports. 2020;10(1):4827.
doi:10.1038/s41598-020-59059-3 .

Buzharevski, Antonio, Paskaš, Svetlana, Sárosi, Menyhárt-Botond, Laube, Markus, Lönnecke, Peter, Neumann, Wilma, Murganić, Blagoje, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Pietzsch, Jens, Hey-Hawkins, Evamarie, "Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells." in Scientific Reports, 10, no. 1 (2020):4827,
https://doi.org/10.1038/s41598-020-59059-3 . .

TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Krajnović, Tamara
AU  - Basile, Maria S.
AU  - Dunđerović, Duško
AU  - Cavalli, Eugenio
AU  - Mangano, Katia
AU  - Mammana, Santa
AU  - Al-Abed, Yousef
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.23020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3339
AB  - The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.
T2  - Molecular Carcinogenesis
T2  - Molecular Carcinogenesis
T1  - Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.
DO  - 10.1002/mc.23020
ER  - 

@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Santa and Al-Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.",
journal = "Molecular Carcinogenesis, Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.",
doi = "10.1002/mc.23020"
}

Paskaš, S., Krajnović, T., Basile, M. S., Dunđerović, D., Cavalli, E., Mangano, K., Mammana, S., Al-Abed, Y., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.. in Molecular Carcinogenesis.
https://doi.org/10.1002/mc.23020

Paskaš S, Krajnović T, Basile MS, Dunđerović D, Cavalli E, Mangano K, Mammana S, Al-Abed Y, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.. in Molecular Carcinogenesis. 2019;.
doi:10.1002/mc.23020 .

Paskaš, Svetlana, Krajnović, Tamara, Basile, Maria S., Dunđerović, Duško, Cavalli, Eugenio, Mangano, Katia, Mammana, Santa, Al-Abed, Yousef, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma." in Molecular Carcinogenesis (2019),
https://doi.org/10.1002/mc.23020 . .

TY  - JOUR
AU  - Buzharevski, Antonio
AU  - Paskaš, Svetlana
AU  - Laube, Markus
AU  - Lönnecke, Peter
AU  - Neumann, Wilma
AU  - Murganić, Blagoje
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Pietzsch, Jens
AU  - Hey-Hawkins, Evamarie
PY  - 2019
UR  - http://pubs.acs.org/doi/10.1021/acsomega.9b00412
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3366
AB  - Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue.
T2  - ACS Omega
T2  - ACS Omega
T1  - Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines
IS  - 5
VL  - 4
DO  - 10.1021/acsomega.9b00412
SP  - 8824
EP  - 8833
ER  - 

@article{
author = "Buzharevski, Antonio and Paskaš, Svetlana and Laube, Markus and Lönnecke, Peter and Neumann, Wilma and Murganić, Blagoje and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Pietzsch, Jens and Hey-Hawkins, Evamarie",
year = "2019",
abstract = "Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue.",
journal = "ACS Omega, ACS Omega",
title = "Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines",
number = "5",
volume = "4",
doi = "10.1021/acsomega.9b00412",
pages = "8824-8833"
}

Buzharevski, A., Paskaš, S., Laube, M., Lönnecke, P., Neumann, W., Murganić, B., Mijatović, S., Maksimović-Ivanić, D., Pietzsch, J.,& Hey-Hawkins, E.. (2019). Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines. in ACS Omega, 4(5), 8824-8833.
https://doi.org/10.1021/acsomega.9b00412

Buzharevski A, Paskaš S, Laube M, Lönnecke P, Neumann W, Murganić B, Mijatović S, Maksimović-Ivanić D, Pietzsch J, Hey-Hawkins E. Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines. in ACS Omega. 2019;4(5):8824-8833.
doi:10.1021/acsomega.9b00412 .

Buzharevski, Antonio, Paskaš, Svetlana, Laube, Markus, Lönnecke, Peter, Neumann, Wilma, Murganić, Blagoje, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Pietzsch, Jens, Hey-Hawkins, Evamarie, "Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines" in ACS Omega, 4, no. 5 (2019):8824-8833,
https://doi.org/10.1021/acsomega.9b00412 . .

TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Krajnović, Tamara
AU  - Basile, Maria S.
AU  - Dunđerović, Duško
AU  - Cavalli, Eugenio
AU  - Mangano, Katia
AU  - Mammana, Sant
AU  - Al‐Abed, Yousef
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3780
AB  - The main focus of this study is exploring the effect and mechanism of two HIVprotease
inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro
growth of melanoma cell lines. NO modification significantly improved the antitumor
potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two
times lower than IC50 values of the parental compound. Our results showed for the
first time, that both compounds induced senescence in primary and metastatic
melanoma cell lines. This transformation was manifested as a change in cell
morphology, enlargement of nuclei, increased cellular granulation, upregulation of
β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive
oxygen species and persistent inhibition of proliferation. The expression of p53, as
one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐
NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event.
The development of senescent phenotype was consistent with the alteration of
the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and
β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir,
could be responsible for a stronger antiproliferative potential of the NO‐modified
compound. Taken together, induction of senescent phenotype may provide an
excellent platform for developing therapeutic approaches based on selective killing of
senescent cells.
PB  - New Jersey: Wiley-VCH Verlag GmbH & Co
T2  - Molecular Carcinogenesis
T1  - Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma
IS  - 8
VL  - 58
DO  - 10.1002/mc.23020
SP  - 1362
EP  - 1375
ER  - 

@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Sant and Al‐Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIVprotease
inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro
growth of melanoma cell lines. NO modification significantly improved the antitumor
potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two
times lower than IC50 values of the parental compound. Our results showed for the
first time, that both compounds induced senescence in primary and metastatic
melanoma cell lines. This transformation was manifested as a change in cell
morphology, enlargement of nuclei, increased cellular granulation, upregulation of
β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive
oxygen species and persistent inhibition of proliferation. The expression of p53, as
one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐
NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event.
The development of senescent phenotype was consistent with the alteration of
the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and
β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir,
could be responsible for a stronger antiproliferative potential of the NO‐modified
compound. Taken together, induction of senescent phenotype may provide an
excellent platform for developing therapeutic approaches based on selective killing of
senescent cells.",
publisher = "New Jersey: Wiley-VCH Verlag GmbH & Co",
journal = "Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma",
number = "8",
volume = "58",
doi = "10.1002/mc.23020",
pages = "1362-1375"
}

Paskaš, S., Krajnović, T., Basile, M. S., Dunđerović, D., Cavalli, E., Mangano, K., Mammana, S., Al‐Abed, Y., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. in Molecular Carcinogenesis
New Jersey: Wiley-VCH Verlag GmbH & Co., 58(8), 1362-1375.
https://doi.org/10.1002/mc.23020

Paskaš S, Krajnović T, Basile MS, Dunđerović D, Cavalli E, Mangano K, Mammana S, Al‐Abed Y, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. in Molecular Carcinogenesis. 2019;58(8):1362-1375.
doi:10.1002/mc.23020 .

Paskaš, Svetlana, Krajnović, Tamara, Basile, Maria S., Dunđerović, Duško, Cavalli, Eugenio, Mangano, Katia, Mammana, Sant, Al‐Abed, Yousef, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma" in Molecular Carcinogenesis, 58, no. 8 (2019):1362-1375,
https://doi.org/10.1002/mc.23020 . .

TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Mazzon, Emanuela
AU  - Basile, Maria Sofia
AU  - Cavalli, Eugenio
AU  - Al-Abed, Yousef
AU  - He, Mingzhu
AU  - Rakočević, Sara
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - http://link.springer.com/10.1007/s10637-019-00733-3
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3261
AB  - We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.
T2  - Investigational New Drugs
T1  - Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.
DO  - 10.1007/s10637-019-00733-3
ER  - 

@article{
author = "Paskaš, Svetlana and Mazzon, Emanuela and Basile, Maria Sofia and Cavalli, Eugenio and Al-Abed, Yousef and He, Mingzhu and Rakočević, Sara and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.",
journal = "Investigational New Drugs",
title = "Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.",
doi = "10.1007/s10637-019-00733-3"
}

Paskaš, S., Mazzon, E., Basile, M. S., Cavalli, E., Al-Abed, Y., He, M., Rakočević, S., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.. in Investigational New Drugs.
https://doi.org/10.1007/s10637-019-00733-3

Paskaš S, Mazzon E, Basile MS, Cavalli E, Al-Abed Y, He M, Rakočević S, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.. in Investigational New Drugs. 2019;.
doi:10.1007/s10637-019-00733-3 .

Paskaš, Svetlana, Mazzon, Emanuela, Basile, Maria Sofia, Cavalli, Eugenio, Al-Abed, Yousef, He, Mingzhu, Rakočević, Sara, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo." in Investigational New Drugs (2019),
https://doi.org/10.1007/s10637-019-00733-3 . .