HSP90 inhibitors(JMackem)

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. Graphical abstract

Among the cytosolic isoforms of HSP90, HSP90α (the inducible isoform) has been observed to be significantly upregulated in both cancer and stress conditions. HSP90α client proteins are required for the proliferation of cancer cells. The inability of HSP90 inhibitors to recognize and bind to specific isoforms of the protein is a major reason for their failure to reach the clinic. In this work, RNA aptamers were selected from a diverse, randomized oligonucleotide library. These were able to bind to HSP90α with significantly higher affinity than HSP90β and inhibit ATPase activity. The two isoforms differ in just two amino acids in their ATP-binding domains. The presence of the aptamers led to decrease in migration of MCF7 breast cancer cells. Significant reduction in the expression of an HSP90α- but not HSP90β-specific client protein was also observed. Aptamers showed significant lethality only on cancer cells, but not on healthy cells. Cell death occurred by apoptosis. Unlike traditional anti-cancer drugs which are inherently toxic and cannot be administered regularly, aptamers offer a promising alternative for prevention of metastasis.