Al-Katib, Ayad; Arnold, Alan A.; Aboukameel, Amro; Sosin, Angela; Smith, Peter; Mohamed, Anwar N.; Beck, Frances W.; Mohammad, Ramzi M. published the artcile< I-kappa-kinase-2 (IKK-2) inhibition potentiates vincristine cytotoxicity in non-Hodgkin's lymphoma>, Category: chlorides-buliding-blocks, the main research area is ML120B vincristine nonHodgkin lymphoma IKK2 NFkappaB anticancer.
Background: 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. 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 mol. inhibitor of IKK-2, ML120B (N-[6-chloro-7-methoxy-9H-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 in vitro using short-term culture assay. We also determined efficacy of the combination in vivo using the SCID mouse xenografts. Results: 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. In vivo, 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. Conclusions: 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.
Molecular Cancer published new progress about Antitumor agents. 6055-19-2 belongs to class chlorides-buliding-blocks, and the molecular formula is C7H17Cl2N2O3P, Category: chlorides-buliding-blocks.
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