Curcumin Toxicity and Inhibition of Oral Fibroblast IL-β-stimulated HGF/SF

Head and neck squamous cell carcinoma (HNSCC) is a common form of cancer worldwide, and represents 5% of cancers diagnosed annually in the U.S. Despite research and treatment advances, survival rates for HNSCC have not improved significantly, creating interest in adjunctive chemotherapies (i.e. curcumin, with anti-inflammatory and anti-cancer properties) that have decreased side effects and toxicity. Tumor- stromal cell interaction (including fibroblasts) is essential for tumor invasion, particularly via hepatocyte growth factor/scatter factor (HGF/SF). IL-1β, which is secreted by carcinoma cells, strongly induces HGF/SF production by fibroblasts.

Objectives: Determine cytotoxic effects of curcumin on human oral fibroblasts, ability of IL-1β to stimulate HGF/SF production, and effects of curcumin on HGF/SF levels.

Method: Normal human oral (gingival) fibroblasts were exposed to curcumin (1-250 µM) or 0.1% DMSO (curcumin diluent) for 1-6 days. Cytotoxicity was assessed by measuring activity of a mitochondrial enzyme. Cells were exposed to rh IL-1β (0.001-10 nM) for 1, 3 or 6 d, ±2 hr-incubation with non-toxic concentrations of curcumin. HGF was measured by ELISA. Data analysis: ANOVA and Scheffe’s F procedure.

Result: : Curcumin (≤ 50 µM) and 0.1% DMSO had no significant cytotoxic effects ≤ 6-d exposure.  IC₅₀values were >250 µM and ~100 µM for 1- and 3-6-day exposure, respectively. Curcumin at ≥ 125 µM caused ≥80% cytotoxicity at ≥ 3-day exposure (p<0.0001). IL-1β caused a dose- and time-dependent stimulation of HGF/SF, significant at [IL-1β ] ≥ 1 nM (p<0.0001). Curcumin (12.5-50 µM) generally caused dose-dependent inhibition of constitutive (p<0.0001) and IL-1β -stimulated (p<0.003) HGF/SF production.

Conclusion: Production of HGF/SF by oral fibroblasts, stimulated by higher IL-1β concentrations, suggests these cells contribute to tumor invasion. Inhibition of HGF/SF by curcumin suggests that it could limit metastatic spread of HNSCC.

(Supported by the UT College of Dentistry Alumni Endowment Fund and the TDA Foundation).