Identification of the ellagitannin geraniin as a novel Hsp90 inhibitor

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone assisting the proper protein folding and assembly, and targeting misfolded proteins to the proteolytic degradation.^{1 – 3} Inhibition of the Hsp90 activity incapacitates simultaneously multiple client proteins, resulting in a blockade of multiple signaling pathways and, ultimately, providing a combinatorial attack to cellular oncogenic processes.⁴ Because of the potential therapeutic use in multiple cancer indications, Hsp90 has emerged as an exciting new target for the development of antitumor agents. 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 Hsp90 similar to 17-(allylamino)-17-demethoxygeldanamycin (17AGG), one of the most potent known anti-Hsp90 agent.

Geraniin was found to inhibit in a dose–dependent manner the Hsp90 ATPase activity, with an inhibitory efficiency similar to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90, monitored by the citrate synthase thermal induced aggregation. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, EGFR was strongly down–regulated in HeLa and Jurkat 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.

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[4] Trepel J. et al. Nat Rev Cancer. 2010, 10, 537 – 549.