Gallic acid (3,4,5-trihydroxybenzoic acid) is a naturally occurring plant phenol obtained by the hydrolysis of tannins and is know to show some pharmacological activities. In screening anti-cancer agents in traditional Chinese medicines, gallic acid was found to show cytotoxicity against all cancer cells that we examined in this study (IC50s: 4.8-13.2 micrograms/ml). Gallic acid was found to show cytotoxicity against primary cultured rat hepatocytes and macrophages, and lesser cytotoxicity against fibroblasts and endothelial cells. Cell death in dRLh-84 cells occurred within 6h after gallic acid treatment at a concentration of more than 20 micrograms/ml. A study of structurally related compounds suggested that the cytotoxicity shown by gallic acid was not a common feature in phenolic compounds, but was a fairly specific characteristic of gallic acid. That is, three adjacent phenolic hydroxyl groups of gallic acid were responsible for the cytotoxicity, and the carboxyl group was not responsible, but seemed to be implicated in distinguishing between normal cells and cancer cells.

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.

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