TY  - CONF
AU  - Ostojić, Marija
AU  - Đurić, Ana
AU  - Srdić-Rajić, Tatjana
AU  - Dobričić, Vladimir
AU  - Grahovac, Jelena
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5477
AB  - Pancreatic ductal adenocarcinoma (PDAC) is the sixth leading cause of death worldwide and the fourth
in Europe with a 5-year survival rate. The common cause of treatment failure in PDAC patients is
multidrug resistance (MDR) due to the increased expression of plasma membrane efflux pumps that
limit the intracellular uptake and retention of numerous xeno- and endobiotics. As the 93.3% of
pancreatic carcinomas expressed P-glycoprotein (P-gp-MDR1/ABCB1) and 31% co-expressed multidrug
resistance protein 1 (MRP1/ABCC1) with MDR1 P-gp, the inhibition of these pumps may be the target
for novel anticancer drugs.
We used the FRED 3.2.0.2 software to predict the affinity of I1-imidazoline receptor ligand rilmenidine
within the binding site of P-gp-MDR1/ABCB1 and MRP1/ABCC1, and flow cytometry to evaluate the
effect of rilmenidine phosphate and rilmenidine fumarate on the efflux pumps in PDAC cells in vitro.
The results of the molecular docking studies indicate that rilmenidine has the binding affinity for both
P-gp-MDR1/ABCB1 and MRP1/ABCC1 efflux pumps. While, in vitro studies show that rilmenidine
fumarate has better potential to inhibit Calcein AM efflux than rilmenidine phosphate, and it did so in a
dose-dependent manner.
Our results indicate that rilmenidine has the affinity to bind to MDR efflux pumps and to inhibit their
activity. This potential of rilmenidine to overcome multidrug resistance in PDAC should be further
investigated in order to develop more effective PDAC therapy.
PB  - COST Action 17104 (STRATAGEM)
C3  - STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal
T1  - Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma
SP  - 80
EP  - 80
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5477
ER  - 

@conference{
author = "Ostojić, Marija and Đurić, Ana and Srdić-Rajić, Tatjana and Dobričić, Vladimir and Grahovac, Jelena",
year = "2022",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is the sixth leading cause of death worldwide and the fourth
in Europe with a 5-year survival rate. The common cause of treatment failure in PDAC patients is
multidrug resistance (MDR) due to the increased expression of plasma membrane efflux pumps that
limit the intracellular uptake and retention of numerous xeno- and endobiotics. As the 93.3% of
pancreatic carcinomas expressed P-glycoprotein (P-gp-MDR1/ABCB1) and 31% co-expressed multidrug
resistance protein 1 (MRP1/ABCC1) with MDR1 P-gp, the inhibition of these pumps may be the target
for novel anticancer drugs.
We used the FRED 3.2.0.2 software to predict the affinity of I1-imidazoline receptor ligand rilmenidine
within the binding site of P-gp-MDR1/ABCB1 and MRP1/ABCC1, and flow cytometry to evaluate the
effect of rilmenidine phosphate and rilmenidine fumarate on the efflux pumps in PDAC cells in vitro.
The results of the molecular docking studies indicate that rilmenidine has the binding affinity for both
P-gp-MDR1/ABCB1 and MRP1/ABCC1 efflux pumps. While, in vitro studies show that rilmenidine
fumarate has better potential to inhibit Calcein AM efflux than rilmenidine phosphate, and it did so in a
dose-dependent manner.
Our results indicate that rilmenidine has the affinity to bind to MDR efflux pumps and to inhibit their
activity. This potential of rilmenidine to overcome multidrug resistance in PDAC should be further
investigated in order to develop more effective PDAC therapy.",
publisher = "COST Action 17104 (STRATAGEM)",
journal = "STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal",
title = "Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma",
pages = "80-80",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5477"
}

Ostojić, M., Đurić, A., Srdić-Rajić, T., Dobričić, V.,& Grahovac, J.. (2022). Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma. in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal
COST Action 17104 (STRATAGEM)., 80-80.
https://hdl.handle.net/21.15107/rcub_farfar_5477

Ostojić M, Đurić A, Srdić-Rajić T, Dobričić V, Grahovac J. Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma. in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal. 2022;:80-80.
https://hdl.handle.net/21.15107/rcub_farfar_5477 .

Ostojić, Marija, Đurić, Ana, Srdić-Rajić, Tatjana, Dobričić, Vladimir, Grahovac, Jelena, "Rilmenidine binds to and inhibits the activity of MDR pumps in pancreatic ductal adenocarcinoma" in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumors, 5th Annual Meeting, 29th June - 1st July 2022, Coimbra, Portugal (2022):80-80,
https://hdl.handle.net/21.15107/rcub_farfar_5477 .

TY  - CONF
AU  - Damjanović, Ana
AU  - Vuković, Miodrag
AU  - Vukadinović, Dragana
AU  - Dobričić, Vladimir
AU  - Grahovac, Jelena
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5450
AB  - Melanoma is one of the most aggressive malignancies, where the prognosis for metastatic patients remains extremely poor. Our group has shown that the antihypertensive drug telmisartan has antimelanoma potential1. Given that the antihypertensive effect is not favorable in cancer patients, the aim of this study was to design and test novel telmisartan derivatives without the angiotensin receptor 1 (AT1R) binding activity. New derivatives were designed by modification of the carboxylic group, in order to alter telmisartan geometry and its AT1R binding properties. Eight derivatives, from which the lack of AT1R antagonistic activity could be expected based on molecular docking, were synthetized and selected for in vitro testing. After the cytotoxicity test on human melanoma cell lines A375 and 518a2, three derivatives that were twice more potent than telmisartan itself were selected for further analysis. The new derivatives induced mitochondrial fragmentation, generation of the mitochondrial reactive oxygen species, and decrease of mitochondrial membrane potential in melanoma cells, the mechanism we previously shown for induction of apoptosis by telmisartan in melanoma cells. As the new derivatives showed more potent effect on melanoma cells than telmisartan these results lay a ground for further preclinical testing in melanoma.
PB  - Croatian Association for Cancer Research, Zagreb, Croatia
C3  - “HDIR-6: Targeting Cancer”, The 6th Meeting of the Croatian Association for Cancer Research with International Participation, November 10-12, 2022, Book of Abstracts
T1  - Antimelanoma Potential of New Telmisartan Analogues Without AT1 Receptor Activity
SP  - 20
EP  - 20
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5450
ER  - 

@conference{
author = "Damjanović, Ana and Vuković, Miodrag and Vukadinović, Dragana and Dobričić, Vladimir and Grahovac, Jelena",
year = "2022",
abstract = "Melanoma is one of the most aggressive malignancies, where the prognosis for metastatic patients remains extremely poor. Our group has shown that the antihypertensive drug telmisartan has antimelanoma potential1. Given that the antihypertensive effect is not favorable in cancer patients, the aim of this study was to design and test novel telmisartan derivatives without the angiotensin receptor 1 (AT1R) binding activity. New derivatives were designed by modification of the carboxylic group, in order to alter telmisartan geometry and its AT1R binding properties. Eight derivatives, from which the lack of AT1R antagonistic activity could be expected based on molecular docking, were synthetized and selected for in vitro testing. After the cytotoxicity test on human melanoma cell lines A375 and 518a2, three derivatives that were twice more potent than telmisartan itself were selected for further analysis. The new derivatives induced mitochondrial fragmentation, generation of the mitochondrial reactive oxygen species, and decrease of mitochondrial membrane potential in melanoma cells, the mechanism we previously shown for induction of apoptosis by telmisartan in melanoma cells. As the new derivatives showed more potent effect on melanoma cells than telmisartan these results lay a ground for further preclinical testing in melanoma.",
publisher = "Croatian Association for Cancer Research, Zagreb, Croatia",
journal = "“HDIR-6: Targeting Cancer”, The 6th Meeting of the Croatian Association for Cancer Research with International Participation, November 10-12, 2022, Book of Abstracts",
title = "Antimelanoma Potential of New Telmisartan Analogues Without AT1 Receptor Activity",
pages = "20-20",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5450"
}

Damjanović, A., Vuković, M., Vukadinović, D., Dobričić, V.,& Grahovac, J.. (2022). Antimelanoma Potential of New Telmisartan Analogues Without AT1 Receptor Activity. in “HDIR-6: Targeting Cancer”, The 6th Meeting of the Croatian Association for Cancer Research with International Participation, November 10-12, 2022, Book of Abstracts
Croatian Association for Cancer Research, Zagreb, Croatia., 20-20.
https://hdl.handle.net/21.15107/rcub_farfar_5450

Damjanović A, Vuković M, Vukadinović D, Dobričić V, Grahovac J. Antimelanoma Potential of New Telmisartan Analogues Without AT1 Receptor Activity. in “HDIR-6: Targeting Cancer”, The 6th Meeting of the Croatian Association for Cancer Research with International Participation, November 10-12, 2022, Book of Abstracts. 2022;:20-20.
https://hdl.handle.net/21.15107/rcub_farfar_5450 .

Damjanović, Ana, Vuković, Miodrag, Vukadinović, Dragana, Dobričić, Vladimir, Grahovac, Jelena, "Antimelanoma Potential of New Telmisartan Analogues Without AT1 Receptor Activity" in “HDIR-6: Targeting Cancer”, The 6th Meeting of the Croatian Association for Cancer Research with International Participation, November 10-12, 2022, Book of Abstracts (2022):20-20,
https://hdl.handle.net/21.15107/rcub_farfar_5450 .

TY  - JOUR
AU  - Rupar, Jelena
AU  - Dobričić, Vladimir
AU  - Grahovac, Jelena
AU  - Radulović, Siniša
AU  - Skok, Žiga
AU  - Ilaš, Janez
AU  - Aleksić, Mara
AU  - Brborić, Jasmina
AU  - Čudina, Olivera
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3606
AB  - A series of eleven 9-acridinyl amino acid derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 cancer cell lines and normal diploid cell line MRC5 using the MTT assay. Compounds 6, 7, 8 and 9 were the most active, with IC50 values comparable to or lower than that of chemotherapeutic agent amsacrine. 8 and 9 were especially effective in the A549 cell line (IC50 ≈ 6 μM), which is of special interest since amsacrine is not sufficiently active in lung cancer patients. Cell cycle analysis revealed that 7 and 9 caused G2/M block, amsacrine caused arrest in the S phase, while 6 and 8 induced apoptotic cell death independently of the cell cycle regulation. In comparison to amsacrine, 6, 7, 8, and 9 showed similar inhibitory potential towards topoisomerase II, whereas only 7 showed DNA intercalation properties. In contrast to amsacrine, 6, 7, 8 and 9 showed a lack of toxicity towards unstimulated normal human leucocytes.
PB  - Royal Society of Chemistry
T2  - RSC Medicinal Chemistry
T1  - Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives
VL  - 11
IS  - 3
SP  - 378
EP  - 386
DO  - 10.1039/c9md00597h
DO  - 2-s2.0-85083014447
ER  - 

@article{
author = "Rupar, Jelena and Dobričić, Vladimir and Grahovac, Jelena and Radulović, Siniša and Skok, Žiga and Ilaš, Janez and Aleksić, Mara and Brborić, Jasmina and Čudina, Olivera",
year = "2020",
abstract = "A series of eleven 9-acridinyl amino acid derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 cancer cell lines and normal diploid cell line MRC5 using the MTT assay. Compounds 6, 7, 8 and 9 were the most active, with IC50 values comparable to or lower than that of chemotherapeutic agent amsacrine. 8 and 9 were especially effective in the A549 cell line (IC50 ≈ 6 μM), which is of special interest since amsacrine is not sufficiently active in lung cancer patients. Cell cycle analysis revealed that 7 and 9 caused G2/M block, amsacrine caused arrest in the S phase, while 6 and 8 induced apoptotic cell death independently of the cell cycle regulation. In comparison to amsacrine, 6, 7, 8, and 9 showed similar inhibitory potential towards topoisomerase II, whereas only 7 showed DNA intercalation properties. In contrast to amsacrine, 6, 7, 8 and 9 showed a lack of toxicity towards unstimulated normal human leucocytes.",
publisher = "Royal Society of Chemistry",
journal = "RSC Medicinal Chemistry",
title = "Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives",
volume = "11",
number = "3",
pages = "378-386",
doi = "10.1039/c9md00597h, 2-s2.0-85083014447"
}

Rupar, J., Dobričić, V., Grahovac, J., Radulović, S., Skok, Ž., Ilaš, J., Aleksić, M., Brborić, J.,& Čudina, O.. (2020). Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives. in RSC Medicinal Chemistry
Royal Society of Chemistry., 11(3), 378-386.
https://doi.org/10.1039/c9md00597h

Rupar J, Dobričić V, Grahovac J, Radulović S, Skok Ž, Ilaš J, Aleksić M, Brborić J, Čudina O. Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives. in RSC Medicinal Chemistry. 2020;11(3):378-386.
doi:10.1039/c9md00597h .

Rupar, Jelena, Dobričić, Vladimir, Grahovac, Jelena, Radulović, Siniša, Skok, Žiga, Ilaš, Janez, Aleksić, Mara, Brborić, Jasmina, Čudina, Olivera, "Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives" in RSC Medicinal Chemistry, 11, no. 3 (2020):378-386,
https://doi.org/10.1039/c9md00597h . .