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The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition

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Abstract

Curcumin, a natural polyphenol, has been described to exhibit effects on signaling pathways, leading to induction of apoptosis. In this study, we observed that curcumin inhibited Hsp90 activity causing depletion of client proteins implicated in survival pathways. Based on this observation, this study was designed to investigate the cellular effects of curcumin combination with the pan-HDAC inhibitors, vorinostat and panobinostat, which induce hyperacetylation of Hsp90, resulting in inhibition of its chaperone function. The results showed that, at subtoxic concentrations, curcumin markedly sensitized tumor cells to vorinostat- and panobinostat-induced growth inhibition and apoptosis. The sensitization was associated with persistent depletion of Hsp90 client proteins (EGFR, Raf-1, Akt, and survivin). In conclusion, our findings document a novel mechanism of action of curcumin and support the therapeutic potential of curcumin/HDAC inhibitors combination, because the synergistic interaction was observed at pharmacologically achievable concentrations, which were ineffective when each drug was used alone.

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Acknowledgments

This work was partially supported by the Associazione Italiana per la Ricerca sul Cancro, Milan, by the Fondazione CARIPLO, Milan, and by the Ministero della Salute (Project Alleanza Contro il Cancro), Rome, Italy.

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Authors and Affiliations

  1. Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy

    Chiara Giommarelli, Valentina Zuco, Enrica Favini & Franco Zunino

  2. Sigma-Tau, 00044, Pomezia (Rome), Italy

    Claudio Pisano

  3. Dipartimento di Scienze Farmaceutiche, Università di Salerno, 84100, Salerno, Italy

    Fabrizio Dal Piaz & Nunziatina De Tommasi

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  1. Chiara Giommarelli
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  2. Valentina Zuco
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Correspondence to Franco Zunino.

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Giommarelli, C., Zuco, V., Favini, E. et al. The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition. Cell. Mol. Life Sci. 67, 995–1004 (2010). https://doi.org/10.1007/s00018-009-0233-x

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  • DOI: https://doi.org/10.1007/s00018-009-0233-x

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