HSP90 inhibition potentiates oxidant-based antimelanoma action of novel thioquercetin derivatives by compromising AhR/CYP1A1 pathway

TL;DR

New thioquercetin compounds show improved anticancer effects against melanoma when combined with HSP90 inhibitors, by increasing oxidative stress and disrupting detoxification pathways.

Contribution

Novel thioquercetin derivatives demonstrate enhanced antimelanoma activity when combined with HSP90 inhibition, revealing a new therapeutic strategy.

Findings

Thioquercetins induce apoptotic cell death in melanoma cells at low micromolar concentrations.

HSP90 inhibition enhances oxidative stress and impairs AhR/CYP1A1 detoxification pathways in melanoma cells.

Thioquercetin derivatives show senolytic activity against cisplatin-induced senescent melanoma cells.

Abstract

Quercetin, a plant-derived dietary flavonoid, has multifunctional biological activities, including anticancer action; however, its applications may be restricted due to limited bioavailability. Thus, novel synthetic quercetin derivatives (QDs) with improved properties and/or drug combinations should be designed and tested. In the present study, anticancer activity of fourteen newly synthesized QDs was investigated using four cellular models of melanoma, namely A375, MM370, G-361, and SH-4 cells. Thioquercetins (thioQ, thioQ(OAc)4, and thioQ(OAc)5), when used at low micromolar range, induced apoptotic cell death in melanoma cells compared to normal cells. Thioquercetins also reduced the population of spheroid-forming cells and suppressed the growth of A375 cells in 3D spheroid models. Thioquercetin-mediated antimelanoma action was potentiated upon heat shock protein 90 (HSP90) inhibition. Co-treatment with the HSP90 inhibitor 17-DMAG and thioquercetins augmented oxidative stress (increased superoxide production, decreased levels of antioxidant proteins SOD1, and PRDX1-2), and impaired the aryl hydrocarbon receptor (AhR)/cytochrome P450 1A1 (CYP1A1) signaling pathway-based detoxification of thioquercetins by the inhibition of AhR translocation to the nucleus and AhR-mediated stimulation of CYP1A1 expression leading to enhanced cytotoxic effects against melanoma cells. The senolytic activity of thioQ(OAc)4 with four acetylated hydroxy groups against cisplatin-induced senescent melanoma cells was also revealed in selected experimental settings. We suggest that the use of novel thioquercetin-based derivatives along with HSP90 inhibitors should be further validated in vivo and considered for the design of more effective antimelanoma strategies in the future.

The online version contains supplementary material available at 10.1007/s10495-026-02311-4.

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