TY  - CONF
AU  - Murganić, Blagoje
AU  - Kazimir, Aleksandar
AU  - Jelača, Sanja
AU  - Tanić, Nikola
AU  - Hey-Hawkins, Evamarie
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12639
AB  - Background: Estrogen receptor-posiƟ ve (ER+) breast cancer accounts for approximately 70% of all cases and, concordantly, anƟ -estrogen therapies present a leading therapeuƟ c choice. InteresƟ ngly, tamoxifen, which is the most commonly used drug, has also been proven eff ecƟ ve in hormone-independent forms of breast cancer, suggesƟ ng the existence of intracellular off -targets. Frequent acquisiƟ on of therapy resistance presents a plaƞ orm for the design of tamoxifen derivaƟ ves with a 2,2’-bipyridine unit enabling the coordinaƟ on of transiƟ on metal moieƟ es, such as copper(II) dichloride. Copper (Cu) is an essenƟ al element involved in the regulaƟ on of cellular growth and development. DisrupƟ on of its delicate homeostasis results in severe toxicity and hard medical condiƟ ons. Increased demand of cancer cells for this micronutrient makes it a valuable candidate for drug design in cancer treatment. The mechanism of acƟ on of Cu complexes is typically based on their ability to induce deadly oxidaƟ ve stress. This study evaluated the effi cacy of a copper–tamoxifen hybrid drug on a panel of breast cancer cell lines with varying receptor expression status. Material and Methods: The viability of breast adenocarcinoma cell lines MCF-7, MDA-MB-361, MDA-MB-231, 4T1 and glioma U251 was esƟ mated by MTT and CV assays. Flow cytometric analysis of cells stained with annexin V-FITC/propidium iodide, ApoStat, acridine orange, dihydrorhodamine 123 (DHR), dihydroethidium (DHE) or 4-amino-5-methylamino-2’,7’-difl uorofl uorescein diacetate (DAF) was used to evaluate cell death, caspase acƟ vity, autophagy, producƟ on of reacƟ ve oxygen and nitrogen species (ROS/RNS), respecƟ vely. Results: The Cu-tamoxifen hybrid drug displayed substanƟ ally higher hormone-receptor (HR) independent cytotoxic acƟ vity compared to previously reported metal complexes with a similar tamoxifen vector. Massive caspase-dependent apoptoƟ c cell death is parƟ ally aƩ enuated by an autophagic process that counteracts death signals. In contrast to the plaƟ num analogue, the copper-based tamoxifen derivaƟ ve reduces ROS/RNS that may be associated with the intracellular accumulaƟ on of the reduced form of CuI which is important for cuproptosis. Conclusion: This study demonstrates the potenƟ al of the copper–tamoxifen hybrid drug as an intriguing alternaƟ ve to commonly used plaƟ num complexes in treatment of cancer. Its safety and effi ciency will be further esƟ mated in vivo
PB  - Belgrade : Serbian Association for Cancer Research
C3  - Oncology Insights
T1  - Potential of Tamoxifen-based Copper(II) Dichloride in Breast Cancer Therapy
IS  - 1
SP  - 95
EP  - 95
UR  - https://hdl.handle.net/21.15107/rcub_vinar_12639
ER  - 

@conference{
author = "Murganić, Blagoje and Kazimir, Aleksandar and Jelača, Sanja and Tanić, Nikola and Hey-Hawkins, Evamarie and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2023",
abstract = "Background: Estrogen receptor-posiƟ ve (ER+) breast cancer accounts for approximately 70% of all cases and, concordantly, anƟ -estrogen therapies present a leading therapeuƟ c choice. InteresƟ ngly, tamoxifen, which is the most commonly used drug, has also been proven eff ecƟ ve in hormone-independent forms of breast cancer, suggesƟ ng the existence of intracellular off -targets. Frequent acquisiƟ on of therapy resistance presents a plaƞ orm for the design of tamoxifen derivaƟ ves with a 2,2’-bipyridine unit enabling the coordinaƟ on of transiƟ on metal moieƟ es, such as copper(II) dichloride. Copper (Cu) is an essenƟ al element involved in the regulaƟ on of cellular growth and development. DisrupƟ on of its delicate homeostasis results in severe toxicity and hard medical condiƟ ons. Increased demand of cancer cells for this micronutrient makes it a valuable candidate for drug design in cancer treatment. The mechanism of acƟ on of Cu complexes is typically based on their ability to induce deadly oxidaƟ ve stress. This study evaluated the effi cacy of a copper–tamoxifen hybrid drug on a panel of breast cancer cell lines with varying receptor expression status. Material and Methods: The viability of breast adenocarcinoma cell lines MCF-7, MDA-MB-361, MDA-MB-231, 4T1 and glioma U251 was esƟ mated by MTT and CV assays. Flow cytometric analysis of cells stained with annexin V-FITC/propidium iodide, ApoStat, acridine orange, dihydrorhodamine 123 (DHR), dihydroethidium (DHE) or 4-amino-5-methylamino-2’,7’-difl uorofl uorescein diacetate (DAF) was used to evaluate cell death, caspase acƟ vity, autophagy, producƟ on of reacƟ ve oxygen and nitrogen species (ROS/RNS), respecƟ vely. Results: The Cu-tamoxifen hybrid drug displayed substanƟ ally higher hormone-receptor (HR) independent cytotoxic acƟ vity compared to previously reported metal complexes with a similar tamoxifen vector. Massive caspase-dependent apoptoƟ c cell death is parƟ ally aƩ enuated by an autophagic process that counteracts death signals. In contrast to the plaƟ num analogue, the copper-based tamoxifen derivaƟ ve reduces ROS/RNS that may be associated with the intracellular accumulaƟ on of the reduced form of CuI which is important for cuproptosis. Conclusion: This study demonstrates the potenƟ al of the copper–tamoxifen hybrid drug as an intriguing alternaƟ ve to commonly used plaƟ num complexes in treatment of cancer. Its safety and effi ciency will be further esƟ mated in vivo",
publisher = "Belgrade : Serbian Association for Cancer Research",
journal = "Oncology Insights",
title = "Potential of Tamoxifen-based Copper(II) Dichloride in Breast Cancer Therapy",
number = "1",
pages = "95-95",
url = "https://hdl.handle.net/21.15107/rcub_vinar_12639"
}

Murganić, B., Kazimir, A., Jelača, S., Tanić, N., Hey-Hawkins, E., Mijatović, S.,& Maksimović-Ivanić, D.. (2023). Potential of Tamoxifen-based Copper(II) Dichloride in Breast Cancer Therapy. in Oncology Insights
Belgrade : Serbian Association for Cancer Research.(1), 95-95.
https://hdl.handle.net/21.15107/rcub_vinar_12639

Murganić B, Kazimir A, Jelača S, Tanić N, Hey-Hawkins E, Mijatović S, Maksimović-Ivanić D. Potential of Tamoxifen-based Copper(II) Dichloride in Breast Cancer Therapy. in Oncology Insights. 2023;(1):95-95.
https://hdl.handle.net/21.15107/rcub_vinar_12639 .

Murganić, Blagoje, Kazimir, Aleksandar, Jelača, Sanja, Tanić, Nikola, Hey-Hawkins, Evamarie, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Potential of Tamoxifen-based Copper(II) Dichloride in Breast Cancer Therapy" in Oncology Insights, no. 1 (2023):95-95,
https://hdl.handle.net/21.15107/rcub_vinar_12639 .

TY  - JOUR
AU  - Tanić, Nikola
AU  - Dramićanin, Tatjana
AU  - Ademović, Nejla
AU  - Tomić, Tijana
AU  - Murganić, Blagoje
AU  - Milovanović, Zorka
AU  - Nedeljković, Milica
AU  - Tanić, Nasta
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12956
AB  - Rak dojke (RD) je najčešći tip maligniteta i vodeći uzrok smrti od raka kod žena širom sveta. RD je izuzetno heterogena bolest i stoga su neophodni različiti modaliteti lečenja da bi se pokrile ove razlike. Cilj našeg istraživanja je bio da se ispita uticaj inaktivacije TP53 i PTEN tumor supresorskih gena (TSG) na odgovor RD na različite modalitete lečenja, kao i njihova moguća saradnja u tome, na postoperativnim uzorcima RD. Metode. Pacijentkinje su klasifikovane, na osnovu primenjene adjuvantne terapije, u četiri različite grupe: one koje su primale samo hormonsku terapiju (HT), hormonsku terapiju u kombinaciji sa hemoterapijom (HT/CHT), hormonsku terapiju u kombinaciji sa hemoterapijom i biološkom terapijom (HT/CHT/H) i druge sistemske terapije koje isključuju HT. Funkcionalna inaktivacija TP53 i PTEN TSG je proučavana analizom mutacionog statusa, gubitka heterozigotnosti (LOH) i metilacionog statusa. Rezultati. Naši rezultati su pokazali da je TP53 gen izmenjen kod 63 od 90 pacijenata (70%), dok je učestalost promena PTEN gena bila nešto niža, 54 od 90 (60%). Simultana inaktivacija je detektovana u 43 testirana uzorka (48%) sa značajnom povezanošću između dva analizirana TSG-a. Dalje, pokazali smo da status TP53 ima značajan uticaj na odgovor pacijenata na terapiju. Suprotno ovome, nismo pokazali značajnu asocijaciju između mutacionog statusa PTEN-a i različitih modaliteta lečenja. Međutim, utvrđena je značajna povezanost između primenjenih terapija i simultanih inaktivacija ova dva TSG-a (p = 0,00001). Zaključak. Pacijenti sa wtTP53 pokazuju značajno bolji terapijski odgovor bez obzira na vrstu terapije u poređenju sa nosiocima mutiranog TP53 gena.
AB  - Introduction. Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples.   Methods. Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG’s were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis.   Results. Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients’ therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001).   Conclusion. Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene.
T2  - Biomedicinska istraživanja
T1  - The impact of TP53 and PTEN tumor suppressor genes on  response to different breast cancer treatment modalities
T1  - Uticaj tumor supresorskih gena TP53 i PTEN na odgovor na različite načine lečenja raka dojke
VL  - 13
IS  - 2
SP  - 105
EP  - 117
DO  - 10.5937/BII2202105T
ER  - 

@article{
author = "Tanić, Nikola and Dramićanin, Tatjana and Ademović, Nejla and Tomić, Tijana and Murganić, Blagoje and Milovanović, Zorka and Nedeljković, Milica and Tanić, Nasta",
year = "2022",
abstract = "Rak dojke (RD) je najčešći tip maligniteta i vodeći uzrok smrti od raka kod žena širom sveta. RD je izuzetno heterogena bolest i stoga su neophodni različiti modaliteti lečenja da bi se pokrile ove razlike. Cilj našeg istraživanja je bio da se ispita uticaj inaktivacije TP53 i PTEN tumor supresorskih gena (TSG) na odgovor RD na različite modalitete lečenja, kao i njihova moguća saradnja u tome, na postoperativnim uzorcima RD. Metode. Pacijentkinje su klasifikovane, na osnovu primenjene adjuvantne terapije, u četiri različite grupe: one koje su primale samo hormonsku terapiju (HT), hormonsku terapiju u kombinaciji sa hemoterapijom (HT/CHT), hormonsku terapiju u kombinaciji sa hemoterapijom i biološkom terapijom (HT/CHT/H) i druge sistemske terapije koje isključuju HT. Funkcionalna inaktivacija TP53 i PTEN TSG je proučavana analizom mutacionog statusa, gubitka heterozigotnosti (LOH) i metilacionog statusa. Rezultati. Naši rezultati su pokazali da je TP53 gen izmenjen kod 63 od 90 pacijenata (70%), dok je učestalost promena PTEN gena bila nešto niža, 54 od 90 (60%). Simultana inaktivacija je detektovana u 43 testirana uzorka (48%) sa značajnom povezanošću između dva analizirana TSG-a. Dalje, pokazali smo da status TP53 ima značajan uticaj na odgovor pacijenata na terapiju. Suprotno ovome, nismo pokazali značajnu asocijaciju između mutacionog statusa PTEN-a i različitih modaliteta lečenja. Međutim, utvrđena je značajna povezanost između primenjenih terapija i simultanih inaktivacija ova dva TSG-a (p = 0,00001). Zaključak. Pacijenti sa wtTP53 pokazuju značajno bolji terapijski odgovor bez obzira na vrstu terapije u poređenju sa nosiocima mutiranog TP53 gena., Introduction. Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples.   Methods. Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG’s were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis.   Results. Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients’ therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001).   Conclusion. Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene.",
journal = "Biomedicinska istraživanja",
title = "The impact of TP53 and PTEN tumor suppressor genes on  response to different breast cancer treatment modalities, Uticaj tumor supresorskih gena TP53 i PTEN na odgovor na različite načine lečenja raka dojke",
volume = "13",
number = "2",
pages = "105-117",
doi = "10.5937/BII2202105T"
}

Tanić, N., Dramićanin, T., Ademović, N., Tomić, T., Murganić, B., Milovanović, Z., Nedeljković, M.,& Tanić, N.. (2022). The impact of TP53 and PTEN tumor suppressor genes on  response to different breast cancer treatment modalities. in Biomedicinska istraživanja, 13(2), 105-117.
https://doi.org/10.5937/BII2202105T

Tanić N, Dramićanin T, Ademović N, Tomić T, Murganić B, Milovanović Z, Nedeljković M, Tanić N. The impact of TP53 and PTEN tumor suppressor genes on  response to different breast cancer treatment modalities. in Biomedicinska istraživanja. 2022;13(2):105-117.
doi:10.5937/BII2202105T .

Tanić, Nikola, Dramićanin, Tatjana, Ademović, Nejla, Tomić, Tijana, Murganić, Blagoje, Milovanović, Zorka, Nedeljković, Milica, Tanić, Nasta, "The impact of TP53 and PTEN tumor suppressor genes on  response to different breast cancer treatment modalities" in Biomedicinska istraživanja, 13, no. 2 (2022):105-117,
https://doi.org/10.5937/BII2202105T . .