I-kappa-kinase-2 (IKK-2) inhibition potentiates vincristine cytotoxicity in non-Hodgkin's lymphoma.

Abstract

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 molecule 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.

• Authors: Ayad Al-Katib, Alan A Arnold, Amro Aboukameel, Angela Sosin, Peter Smith, Anwar N Mohamed, Frances W Beck, Ramzi M Mohammad
• Journal: Molecular cancer (Mol Cancer) Vol. 9 Pg. 228 (Sep 01 2010) ISSN: 1476-4598 [Electronic] England
• PMID: 20809973 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antitussive Agents
• Enzyme Inhibitors
• Niacinamide
• Vincristine
• Doxorubicin
• Cyclophosphamide
• I-kappa B Kinase

Topics

• Animals
• Antitussive Agents (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cyclophosphamide (therapeutic use)
• Doxorubicin (therapeutic use)
• Enzyme Inhibitors (therapeutic use)
• Female
• Flow Cytometry
• Humans
• I-kappa B Kinase (antagonists & inhibitors)
• Lymphoma, Large B-Cell, Diffuse (drug therapy)
• Lymphoma, Non-Hodgkin (drug therapy)
• Mice
• Mice, SCID
• Microscopy, Fluorescence
• Niacinamide (analogs & derivatives, therapeutic use)
• Vincristine (therapeutic use)
• Xenograft Model Antitumor Assays