TY  - JOUR
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Jovanović, Mirna
AU  - Musso, Loana
AU  - Tsakovska, Ivanka
AU  - Pajeva, Ilza
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2019
UR  - https://www.mdpi.com/1422-0067/20/18/4575
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3476
AB  - Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.
T2  - International Journal of Molecular Sciences
T1  - Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.
IS  - 18
VL  - 20
DO  - 10.3390/ijms20184575
SP  - 4575
ER  - 

@article{
author = "Dinić, Jelena and Podolski-Renić, Ana and Jovanović, Mirna and Musso, Loana and Tsakovska, Ivanka and Pajeva, Ilza and Dallavalle, Sabrina and Pešić, Milica",
year = "2019",
abstract = "Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.",
journal = "International Journal of Molecular Sciences",
title = "Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.",
number = "18",
volume = "20",
doi = "10.3390/ijms20184575",
pages = "4575"
}

Dinić, J., Podolski-Renić, A., Jovanović, M., Musso, L., Tsakovska, I., Pajeva, I., Dallavalle, S.,& Pešić, M.. (2019). Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.. in International Journal of Molecular Sciences, 20(18), 4575.
https://doi.org/10.3390/ijms20184575

Dinić J, Podolski-Renić A, Jovanović M, Musso L, Tsakovska I, Pajeva I, Dallavalle S, Pešić M. Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.. in International Journal of Molecular Sciences. 2019;20(18):4575.
doi:10.3390/ijms20184575 .

Dinić, Jelena, Podolski-Renić, Ana, Jovanović, Mirna, Musso, Loana, Tsakovska, Ivanka, Pajeva, Ilza, Dallavalle, Sabrina, Pešić, Milica, "Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells." in International Journal of Molecular Sciences, 20, no. 18 (2019):4575,
https://doi.org/10.3390/ijms20184575 . .