Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

Abstract

Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90) binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90α similar to that of 17-(allylamino)-17-demethoxygeldanamycin (17AGG). Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose−dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down−regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors.

Targeting apoptosis via inactivation of PI3K/Akt/mTOR signaling pathway involving NF-κB by geraniin in HT-29 human colorectal adenocarcinoma cells

“…The current findings showed that geraniin resulted in a significant timedependent suppression of phosphorylated Akt proteins with a concomitant decreased ratio of p-Akt/Akt. This phenomenon was in accordance with the previous study showing that geraniin exhibited significant dose-depen-dent reduction of p-Akt in both Jurkat and HepG2 cells [48] . Activated Akt leads to the survival of tumor and attenuates apoptosis via phosphorylation of multiple downstream targets including mTOR and GSK-3β.…”

Targeting the Hsp90 C-terminal domain by the chemically accessible dihydropyrimidinone scaffold

“…Under the same experimental conditions, IC 50 values for 17-AAG treatment were 2.1 AE 0.3 mM in A375 and 9.6 AE 0.15 mM in Jurkat cell lines, in agreement with those reported by Dal Piaz et al 19 and Liu et al 20 Interestingly, the cytotoxic effect found for compound 1 was in line with SPR analyses, which disclosed 1 as one of the most efficient binders to the immobilized recombinant Hsp90a (K D of 76 AE 7 nM). Compound 17 exhibited IC 50 values of 150 AE 0.3 mM in both cancer cell lines, while 2, 6-8 and 12 had no cytotoxicity.…”

“…19,23 The proteolytic patterns obtained, performed both on Hsp90a and on the Hsp90a/1 complex, using trypsin or chymotrypsin as proteolytic agents, are summarized in Fig. 19,23 The proteolytic patterns obtained, performed both on Hsp90a and on the Hsp90a/1 complex, using trypsin or chymotrypsin as proteolytic agents, are summarized in Fig.…”

Geraniin Inhibits LPS-Induced THP-1 Macrophages Switching to M1 Phenotype via SOCS1/NF-κB Pathway

“…Geraniin is a polyphenolic compound that has a wide range of bioactive properties, including anti-oxidant activity, protecting from infections, exerting immunological effects, and inducing metabolic changes [13]. Several studies have demonstrated that geraniin suppresses lung cancer by inhibiting the TGF-β1-induced epithelial-mesenchymal transition [14], exerts a protective effect against osteoporosis in ovariectomized rats [15], and inhibits the chaperone activity of Hsp90 thus providing a multi-targeted approach against cellular oncogenic processes [16]. In our previous studies, geraniin showed efficient radical scavenging activities, including scavenging of superoxide and DPPH radicals, as well as an excellent reducing power [17].…”