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Open AccessArticle

Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells

1
Department of Neurobiology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
2
Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy
3
Department of QSAR and Molecular Modelling, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 105, 1113 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4575; https://doi.org/10.3390/ijms20184575
Received: 18 July 2019 / Revised: 31 August 2019 / Accepted: 6 September 2019 / Published: 16 September 2019
(This article belongs to the Special Issue Molecular Chaperones 2.0)
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. View Full-Text
Keywords: isoxazolonaphthoquinones; Hsp90 inhibitors; P-glycoprotein inhibitors; cancer; multidrug resistance isoxazolonaphthoquinones; Hsp90 inhibitors; P-glycoprotein inhibitors; cancer; multidrug resistance
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MDPI and ACS Style

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. Int. J. Mol. Sci. 2019, 20, 4575.

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