Combining Curcumin (Diferuloylmethane) and Heat Shock Protein Inhibition for Neurofibromatosis 2 Treatment: Analysis of Response and Resistance Pathways

Abstract

Neurofibromatosis type 2 (NF2) is a genetic condition characterized by inactivation of the NF2 tumor suppressor gene and the development of schwannomas. The NF2 gene product, merlin, is activated (dephosphorylated) by contact inhibition and promotes growth suppression. We investigated the effect of curcumin (diferuloylmethane), a molecule with anti-inflammatory and antitumorigenic properties, on human schwannoma cell growth and the regulation of merlin by curcumin in both NF2 cells and neuroblastoma (non-NF2) cells. Curcumin inhibited the growth of HEI-193 schwannoma cells in vitro and downregulated the phosphorylation of Akt and extracellular signal-regulated kinase 1/2. Curcumin also activated MYPT1-pp1d (a merlin phosphatase), which was associated with dephosphorylation of merlin on serine 518, an event that results in the folding of merlin to its active conformation. In addition, curcumin induced apoptosis and generated reactive oxygen species in HEI-193 cells. Consequently, hsp70 was upregulated at the mRNA and protein levels, possibly serving as a mechanism of escape from curcumin-induced apoptosis and growth inhibition. Endogenous merlin and hsp70 proteins interacted in HEI-193 schwannoma and SK-N-AS neuroblastoma cells. The combination of curcumin and an hsp inhibitor synergistically suppressed schwannoma cell growth. Our results provide a rationale for combining curcumin and KNK437 in the treatment of NF2.

Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2

“…However, a recent study reported the coimmunoprecipitation of merlin with HSP70, which forms a multichaperone complex with HSP90 (21), implying that merlin may be regulated by or involved in the function of this complex. Identification of potential specificity of HSP90 inhibition in the NF2-deficient tumors will be the next step of the study.…”

“…A study showed that the HSP90 complexes in tumor cells possess greater affinity to an HSP90 inhibitor 17-AAG, thereby promising selectivity for targeting tumor cells over normal cells (20). There is single report suggesting the efficacy of HSP90 inhibition in NF2 (21). Many known client proteins of HSP90 were found to be coactivated in human NF2-related tumors, such as ERBBs, AKT, and MET (refs.…”

Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting Heat Shock Protein 90 Expression

“…MM cells express highly active NF-κB, and bortezomib inhibits tumor growth mainly by blocking the NF-κB signaling pathway [10]. This study showed that low concentrations of bortezomib did not affect NF-κB expression levels significantly, explaining the absence of both induced apoptosis and inhibition of proliferation.…”

Natural Compounds as Potential Treatments of NF2-Deficient Schwannoma and Meningioma

“…Caffeic acid phenethyl ester (CAPE)-based extracts and artepillin C-based propolis from bee wax have been shown to suppress the growth of an NF1 -deficient malignant peripheral nerve sheath tumor cell line and a human papillomavirus E6/7 oncogene-immortalized vestibular schwannoma cell line, HEI-193 18–19 ; however, the mechanisms by which CAPE and artepillin C suppress tumor growth are not understood. Curcumin found in turmeric, a spice derived from the rhizomes of Curcuma longa of the ginger family, was found to inhibit the growth of HEI-193 cells by down-regulating the phosphorylation of AKT and ERK1/2 20 . Honokiol, a lignan found in Magnolia grandiflora was also shown to exhibit antiproliferative activity in HEI-193 and inhibit ERK phosphorylation 21 .…”