title: 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-pp1δ (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.
authors: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Laura S
authors: LS
authors: Angelo
authors: Ji Yuan
authors: JY
authors: Wu
authors: Feng
authors: F
authors: Meng
authors: Michael
authors: M
authors: Sun
authors: Scott
authors: S
authors: Kopetz
authors: Ian E
authors: IE
authors: McCutcheon
authors: John M
authors: JM
authors: Slopis
authors: Razelle
authors: R
authors: Kurzrock
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D016518:Neurofibromatosis 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D025581:Neurofibromin 2 / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001559:Benzhydryl Compounds; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C410027:KNK 437; D025581:Neurofibromin 2; D011760:Pyrrolidinones; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D003474:Curcumin