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

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.

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

“…The stimulatory effects of curcumin on levels of select HSPs may in part be explained by HSP90 binding and/or inhibitory activity (59). HSP90 inhibition typically increases HSP90 and HSP70 levels via feedback to HSF-1 (15).…”

“…Furthermore, similar levels of brain curcumin did not increase HSP levels in wildtype mice (not shown). Thus, curcumin may act via an alternative mechanism selectively altering HSP90 co-chaperone interactions, for example through a high affinity (6 nM) HSP90 binding site of unknown function (59).…”

HDAC Inhibitors Augmented Cell Migration and Metastasis through Induction of PKCs Leading to Identification of Low Toxicity Modalities for Combination Cancer Therapy

“…For example, there are results showing that HDACi can enhance the antitumor effects of curcumin and tamoxifen in human cancer cells through HDACi epigenetic modulation and/or posttranslational modification (ex. acetylation) of the heat shock protein 90 (Hsp90) and estrogen receptor, respectively (47,48). With the concept of HDACi to reverse the tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer, a recent phase II clinical trial of estrogen receptor-positive patients with metastatic breast cancer who received at least one prior aromatase inhibitor treatment were selected for combination therapy of SAHA/tamoxifen (48).…”

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…Numerous studies on the effects of curcumin on ErbB signaling found reduced protein levels of ErbB-1 (Chen and Xu, 2005;Chen et al, 2006a;Patel et al, 2008;Somers-Edgar et al, 2008;Thangapazham et al, 2008b;Majumdar et al, 2009;Giommarelli et al, 2010;Lee et al, 2011a;Nautiyal et al, 2011a), ErbB-2 Ohori et al, 2006;Thangapazham et al, 2008b;Majumdar et al, 2009;Nautiyal et al, 2011a), and ErbB-3 (Majumdar et al, 2009;Nautiyal et al, 2011a), as well as reduced phosphorylation of ErbB proteins (Chen and Xu, 2005;Reddy et al, 2006;Somers-Edgar et al, 2008;Khafif et al, 2009;Majumdar et al, 2009) after incubation of cells with curcumin. It should be noted that the effects of curcumin on ErbB levels and function varied per cancer cell type (Squires et al, 2003;Kim et al, 2006;Reddy et al, 2006;LevAri et al, 2007;Khafif et al, 2009;Lin et al, 2009).…”