Curcumin‐induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IκB kinase and nuclear factor κB activity and are independent of the B‐Raf/mitogen‐activated/extracellular signal‐regulated protein kinase pathway and the Akt pathway

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Abstract
BACKGROUND Nuclear factor‐κB (NF‐κB) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF‐κB for melanoma treatment by using curcumin, an agent with known, potent, NF‐κB‐inhibitory activity and little toxicity in humans. METHODS Three melanoma cell lines (C32, G‐361, and WM 266‐4), all of which had B‐raf mutations, were treated with curcumin, and the authors assessed its effects on viability ((3‐[4,5‐dimethylthiazol‐2‐yl]2,5‐diphenyltetrazolium bromide assay) and apoptosis (flow‐cytometric analysis of annexin V/propidium iodide‐stained cells). Curcumin‐treated cells also were examined for NF‐κB binding activity (electrophoretic mobility shift assay) and for the activity of its upstream regulator, IκB kinase (IKK) (immune complex kinase assay). In addition, relevant signaling, as reflected by B‐Raf kinase activity (kinase cascade assay), and steady‐state levels of activated, downstream effectors, as reflected by mitogen‐activated signal‐regulated protein kinase (MEK), extracellular signal‐regulated protein kinase (ERK), and Akt phosphorylation levels (immunoblots), were assessed. RESULTS Curcumin treatment decreased cell viability of all 3 cell lines in a dose‐dependent manner (50% inhibitory concentration = 6.1–7.7 μM) and induced apoptosis. NF‐κB and IKK were active constitutively in all melanoma cell lines examined, and curcumin, under apoptosis‐inducing conditions, down‐regulated NF‐κB and IKK activities. However, curcumin did not inhibit the activities of B‐Raf, MEK, or ERK, and Akt phosphorylation was enhanced. Furthermore, in the presence of curcumin, the Akt inhibitor 1L‐6‐hydroxymethyl‐chiro‐inositol 2‐[(R)‐2‐O‐methyl‐3‐O‐octadecylcarbonate] no longer suppressed Akt phosphorylation. CONCLUSIONS Curcumin has potent antiproliferative and proapoptotic effects in melanoma cells. These effects were associated with the suppression of NF‐κB and IKK activities but were independent of the B‐Raf/MEK/ERK and Akt pathways. Cancer 2005. © 2005 American Cancer Society.