Inhibition of pro-inflammatory cytokines in tumour associated macrophages is a potential anti-cancer mechanism of carboxyamidotriazole

Carboxyamidotriazole (CAI) has not only direct anti-cancer activities, but also anti-inflammation effects in a variety of inflammatory animal models. In the present study, we investigated whether macrophages, which are important both in cancer and inflammation, could be regulated by CAI. The results showed that CAI could inhibit tumour necrosis factor-α (TNF-α) production in macrophages in various environments, including those isolated from peritoneal cavity of adjuvant-induced arthritis (AA) rats, from Lewis lung carcinoma (LLC) transplanted tumours and those induced by LLC cells in vitro. Dexamethasone (DEX), one of the pro-inflammatory cytokines inhibitors, could enhance CAI's inhibition of LLC cells proliferation and invasion in macrophages and LLC cells co-culture systems, as well as the tumour growth in vivo. However, DEX failed to enhance CAI's inhibition of LLC cells proliferation when LLC cells were cultured alone, suggesting that the combination of CAI and DEX exerted great anti-tumour effects probably by acting on macrophages in the tumour environment. Over all, we found CAI could act on macrophages and regulate the production of TNF-α not only in inflammatory diseases but also in tumour microenvironment, which might be another anti-tumour mechanism of CAI.