TY  - JOUR
AU  - Hicke, Francisco
AU  - Puerta, Adrián
AU  - Dinić, Jelena
AU  - Pešić, Milica
AU  - Padrón, José M.
AU  - López, Óscar
AU  - Fernández-Bolaños, José G.
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4671
AB  - The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents.
We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondria-directed vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol).
Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 μM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269).
The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp.
Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane.
Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon co-administration with a pump-efflux inhibitor.
PB  - Amsterdam : Elsevier Ltd
T2  - European Journal of Medicinal Chemistry
T1  - Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents
VL  - 228
DO  - 10.1016/j.ejmech.2021.113980
SP  - 113980
ER  - 

@article{
author = "Hicke, Francisco and Puerta, Adrián and Dinić, Jelena and Pešić, Milica and Padrón, José M. and López, Óscar and Fernández-Bolaños, José G.",
year = "2022",
abstract = "The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents.
We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondria-directed vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol).
Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 μM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269).
The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp.
Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane.
Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon co-administration with a pump-efflux inhibitor.",
publisher = "Amsterdam : Elsevier Ltd",
journal = "European Journal of Medicinal Chemistry",
title = "Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents",
volume = "228",
doi = "10.1016/j.ejmech.2021.113980",
pages = "113980"
}

Hicke, F., Puerta, A., Dinić, J., Pešić, M., Padrón, J. M., López, Ó.,& Fernández-Bolaños, J. G.. (2022). Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents. in European Journal of Medicinal Chemistry
Amsterdam : Elsevier Ltd., 228, 113980.
https://doi.org/10.1016/j.ejmech.2021.113980

Hicke F, Puerta A, Dinić J, Pešić M, Padrón JM, López Ó, Fernández-Bolaños JG. Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents. in European Journal of Medicinal Chemistry. 2022;228:113980.
doi:10.1016/j.ejmech.2021.113980 .

Hicke, Francisco, Puerta, Adrián, Dinić, Jelena, Pešić, Milica, Padrón, José M., López, Óscar, Fernández-Bolaños, José G., "Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents" in European Journal of Medicinal Chemistry, 228 (2022):113980,
https://doi.org/10.1016/j.ejmech.2021.113980 . .

TY  - JOUR
AU  - Dinić, Jelena
AU  - Efferth, Thomas
AU  - García-Sosa, Alfonso T.
AU  - Grahovac, Jelena
AU  - Padrón, José M.
AU  - Pajeva, Ilza
AU  - Rizzolio, Flavio
AU  - Saponara, Simona
AU  - Spengler, Gabriella
AU  - Tsakovska, Ivanka
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3758
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3767
AB  - Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.
PB  - Churchill Livingstone
T2  - Drug Resistance Updates
T1  - Repurposing old drugs to fight multidrug resistant cancers
VL  - 52
DO  - 10.1016/j.drup.2020.100713
SP  - 100713
ER  - 

@article{
author = "Dinić, Jelena and Efferth, Thomas and García-Sosa, Alfonso T. and Grahovac, Jelena and Padrón, José M. and Pajeva, Ilza and Rizzolio, Flavio and Saponara, Simona and Spengler, Gabriella and Tsakovska, Ivanka",
year = "2020",
abstract = "Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.",
publisher = "Churchill Livingstone",
journal = "Drug Resistance Updates",
title = "Repurposing old drugs to fight multidrug resistant cancers",
volume = "52",
doi = "10.1016/j.drup.2020.100713",
pages = "100713"
}

Dinić, J., Efferth, T., García-Sosa, A. T., Grahovac, J., Padrón, J. M., Pajeva, I., Rizzolio, F., Saponara, S., Spengler, G.,& Tsakovska, I.. (2020). Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates
Churchill Livingstone., 52, 100713.
https://doi.org/10.1016/j.drup.2020.100713

Dinić J, Efferth T, García-Sosa AT, Grahovac J, Padrón JM, Pajeva I, Rizzolio F, Saponara S, Spengler G, Tsakovska I. Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates. 2020;52:100713.
doi:10.1016/j.drup.2020.100713 .

Dinić, Jelena, Efferth, Thomas, García-Sosa, Alfonso T., Grahovac, Jelena, Padrón, José M., Pajeva, Ilza, Rizzolio, Flavio, Saponara, Simona, Spengler, Gabriella, Tsakovska, Ivanka, "Repurposing old drugs to fight multidrug resistant cancers" in Drug Resistance Updates, 52 (2020):100713,
https://doi.org/10.1016/j.drup.2020.100713 . .

TY  - JOUR
AU  - Dinić, Jelena
AU  - Efferth, Thomas
AU  - García-Sosa, Alfonso T.
AU  - Grahovac, Jelena
AU  - Padrón, José M.
AU  - Pajeva, Ilza
AU  - Rizzolio, Flavio
AU  - Saponara, Simona
AU  - Spengler, Gabriella
AU  - Tsakovska, Ivanka
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3758
AB  - Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.
PB  - Churchill Livingstone
T2  - Drug Resistance Updates
T1  - Repurposing old drugs to fight multidrug resistant cancers
VL  - 52
DO  - 10.1016/j.drup.2020.100713
SP  - 100713
ER  - 

@article{
author = "Dinić, Jelena and Efferth, Thomas and García-Sosa, Alfonso T. and Grahovac, Jelena and Padrón, José M. and Pajeva, Ilza and Rizzolio, Flavio and Saponara, Simona and Spengler, Gabriella and Tsakovska, Ivanka",
year = "2020",
abstract = "Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.",
publisher = "Churchill Livingstone",
journal = "Drug Resistance Updates",
title = "Repurposing old drugs to fight multidrug resistant cancers",
volume = "52",
doi = "10.1016/j.drup.2020.100713",
pages = "100713"
}

Dinić, J., Efferth, T., García-Sosa, A. T., Grahovac, J., Padrón, J. M., Pajeva, I., Rizzolio, F., Saponara, S., Spengler, G.,& Tsakovska, I.. (2020). Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates
Churchill Livingstone., 52, 100713.
https://doi.org/10.1016/j.drup.2020.100713

Dinić J, Efferth T, García-Sosa AT, Grahovac J, Padrón JM, Pajeva I, Rizzolio F, Saponara S, Spengler G, Tsakovska I. Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates. 2020;52:100713.
doi:10.1016/j.drup.2020.100713 .

Dinić, Jelena, Efferth, Thomas, García-Sosa, Alfonso T., Grahovac, Jelena, Padrón, José M., Pajeva, Ilza, Rizzolio, Flavio, Saponara, Simona, Spengler, Gabriella, Tsakovska, Ivanka, "Repurposing old drugs to fight multidrug resistant cancers" in Drug Resistance Updates, 52 (2020):100713,
https://doi.org/10.1016/j.drup.2020.100713 . .