Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.
2019
Аутори:
Dinić, JelenaPodolski-Renić, Ana
Jovanović, Mirna
Musso, Loana
Tsakovska, Ivanka
Pajeva, Ilza
Dallavalle, Sabrina
Pešić, Milica
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
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.
Кључне речи:
Hsp90 inhibitors; P-glycoprotein inhibitors; Cancer; Isoxazolonaphthoquinones; Multidrug resistanceИзвор:
International Journal of Molecular Sciences, 2019, 20, 18, 4575-Финансирање / пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- National Science Fund of Bulgaria, grant number KP-06-COST/3/18.06.2019
- CA17104 STRATAGEM
DOI: 10.3390/ijms20184575
PubMed: 31527404