Curcumin, a medicinal herbal compound capable of inducing the heat shock response

Objective: There is interest in developing pharmacologic inducers of the he at shock response as a means to confer cytoprotection in the clinical setti ng. We propose that a potential strategy for screening novel pharmacologic inducers of the heat shock response is to examine known inhibitors of the t ranscription factor nuclear factor-kappaB. Curcumin, derived from the tropi cal herb Curcuma longa, is a recently described inhibitor of nuclear factor -KB and is widely used in Eastern medicinal practices. We tested the hypoth esis that curcumin can induce expression of heat shock protein 70. Design. Experimental. Setting. University laboratory. Subjects: HeLa cells, Interventions. HeLa cells were exposed to varying concentrations of curcumi n and analyzed for expression of heat shock protein 70 by Western blot. Measurements and Main Results; Activation of the transcription factor, heat shock factor-1, was analyzed by electromobility shift assays. Curcumin-med iated inhibition of nuclear factor-kappaB activation was measured by transi ently transfecting cells with a nuclear factor-KB luciferase reporter plasm id. The role of heat shock factor-1 in curcumin-mediated expression of heat shock protein 70 was tested in embryonic fibroblasts derived from heat sho ck factor-1 knockout mice. Induction of the heat shock response was quantif ied by transiently transfecting cells with a heat shock protein 70 promoter -luciferase reporter plasmid. Cell viability was measured by using the tetr azolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide a ssay. Curcumin induced expression of heat shock protein 70, the major induc ible heat shock protein in cells undergoing the heat shock response, in a d ose-dependent and time-dependent manner. Curcumin induced specific nuclear translocation and activation of heat shock factor-1. Curcumin-mediated expr ession of heat shock protein 70 was reduced substantially in fibroblasts ha ving genetic ablation of heat shock factor-1. The extent of induction of th e heat shock response correlated, in part, with cellular toxicity. Conclusions: Curcumin, a widely used medicinal compound, induces the heat s hock response in vitro as measured by expression of heat shock protein 70, The mechanism of heat shock protein 70 induction depends on activation of h eat shock factor-1. Examining known inhibitors of nuclear factor-kappaB for their ability to induce heat shock protein 70 may be a valid screening met hod to discover novel pharmacologic inducers of the heat shock response.