I-<it>kappa</it>-kinase-2 (IKK-2) inhibition potentiates vincristine cytotoxicity in non-Hodgkin's lymphoma

• Main Authors: Al-Katib Ayad, Arnold Alan A, Aboukameel Amro, Sosin Angela, Smith Peter, Mohamed Anwar N, Beck Frances W, Mohammad Ramzi M
• Format: Article
• Language: English
• Published: BMC 2010-09-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/9/1/228

<p>Abstract</p> <p>Background</p> <p>IKK-2 is an important regulator of the nuclear factor-κB (NF-κB) which has been implicated in survival, proliferation and apoptosis resistance of lymphoma cells. In this study, we investigated whether inhibition of IKK-2 impacts cell growth or cytotoxicity of selected conventional chemotherapeutic agents in non-Hodgkin's lymphoma.</p> <p>Two established model systems were used; Follicular (WSU-FSCCL) and Diffuse Large Cell (WSU-DLCL2) Lymphoma, both of which constitutively express p-IκB. A novel, selective small molecule inhibitor of IKK-2, ML120B (<it>N</it>-[6-chloro-<it>7</it>-methoxy-<it>9H</it>-β-carbolin-8-yl]-2-methylnicotinamide) was used to perturb NF-κB in lymphoma cells. The growth inhibitory effect of ML120B (M) alone and in combination with cyclophosphamide monohydrate (C), doxorubicin (H) or vincristine (V) was evaluated <it>in vitro </it>using short-term culture assay. We also determined efficacy of the combination <it>in vivo </it>using the SCID mouse xenografts.</p> <p>Results</p> <p>ML120B down-regulated p-IκBα protein expression in a concentration dependent manner, caused growth inhibition, increased G0/G1 cells, but did not induce apoptosis. There was no significant enhancement of cell kill in the M/C or M/H combination. However, there was strong synergy in the M/V combination where the vincristine concentration can be lowered by a hundred fold in the combination for comparable G2/M arrest and apoptosis. ML120B prevented vincristine-induced nuclear translocation of p65 subunit of NF-κB. <it>In vivo</it>, ML120B was effective by itself and enhanced CHOP anti-tumor activity significantly (P = 0.001) in the WSU-DLCL2-SCID model but did not prevent CNS lymphoma in the WSU-FSCCL-SCID model.</p> <p>Conclusions</p> <p>For the first time, this study demonstrates that perturbation of IKK-2 by ML120B leads to synergistic enhancement of vincristine cytotoxicity in lymphoma. These results suggest that disruption of the NF-κB pathway is a useful adjunct to cytotoxic chemotherapy in lymphoma.</p>