Suppression of tumor necrosis factor-alpha-induced nuclear factor kappaB activation and aromatase activity by capsaicin and its analog capsazepine.

摘要

Target-specific drugs, including natural products, offer promise for the amelioration of cancer and other human ailments. Capsaicin, the pungent ingredient present in chilies (Capsicum annuum L.), and capsazepine, a synthetic analog of capsaicin (collectively referred to as vanilloids), are known to possess a variety of pharmacological and physiological properties. In our continuous effort to discover and characterize cancer chemopreventive agents from natural products, we investigated the effect of vanilloids on nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) activation using stably transfected 293/NFkappaB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor-alpha (TNFalpha) and on aromatase activity. Capsaicin and capsazepine blocked TNFalpha-induced NFkappaB activation in a dose-dependent manner with 50 inhibitory concentration (IC(50)) values of 0.68 and 4.2 muM, respectively. No significant cytotoxicity was observed at the highest concentrations tested (53.1 muM for capsazepine and 65.5 muM for capsaicin). In addition, these vanilloids inhibited aromatase activity with IC(50) values of 13.6 and 8.8 muM, respectively. Computer-aided molecular docking studies showed docking scores indicative of good binding affinity of vanilloids with aromatase and NFkappaB. The highly conserved residues for capsaicin and capsazepine binding with NFkappaB p50 were Ser299 and Ile278 (H-bond 2.81A) and with NFkappaB p100 were Ser6, Arg82, Val86, Arg90 (H-bond 2.89A), Gly4, and Ser2 (H-bond 2.81A). The amino acids Trp224, Arg435, and Val373 (H-bond 2.80A) were found to be important for the binding of capsaicin and capsazepine with aromatase. Based on these findings, aromatase and NFkappaB are suggested as valid targets for these compounds; additional investigation of chemopreventive or chemotherapeutic potential is required.