Curcumin (diferuloylmethane) inhibits constitutive NF-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma

Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin's lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL's resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappa B regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappa B in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappa B and I kappa B kinase and phosphorylated forms of I kappa B alpha and p65. This correlated with expression of TNF, I kappa B alpha, Bcl-2, Bcl-x1, COX-2 and IL-6, all regulated by NF-kappa B. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappa B and inhibited the consitutively active I kappa B alpha kinase (IKK), and phosphorylation of I kappa B alpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappa B-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PAR-P cleavage, and annexin V staining. That NF-kappa B activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappa B complex and inhibited the proliferation of MCL cells. Constitutive NF-kappa B activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappa B activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappa B and IKK leading to suppression of expression of NF-kappa B-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL. (c) 2005 Elsevier Inc. All rights reserved.