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

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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.

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Most cited references 33

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Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

P Talalay, T C Chou (1984)

A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.

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A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

W.C. Chan, F. Cavalli, P Jacobs … (1997)

The recognition of several new types of non-Hodgkin's lymphoma (NHL) in recent years has led to proposals for changing lymphoma classifications, including a new proposal put forth by the International Lymphoma Study Group (ILSG). However, the clinical significance of the new entities and the practical utility of this new proposal have not been studied. Therefore, we performed a clinical evaluation of the ILSG classification. A cohort of 1,403 cases of NHL was organized at nine study sites around the world and consisted of consecutive patients seen between 1988 and 1990 who were previously untreated. A detailed protocol for histologic and clinical analysis was followed at each site, and immunologic characterization as to T- or B-cell phenotype was required. Five expert hematopathologists visited the sites and each classified each case using the ILSG classification. A consensus diagnosis was also reached in each case, and each expert rereviewed a 20% random sample of the cases. Clinical correlations and survival analyses were then performed. A diagnosis of NHL was confirmed in 1,378 (98.2%) of the cases. The most common lymphoma types were diffuse large B-cell lymphoma (31%) and follicular lymphoma (22%), whereas the new entities comprised 21% of the cases. Diagnostic accuracy was at least 85% for most of the major lymphoma types, and reproducibility of the diagnosis was 85%. Immunophenotyping improved the diagnostic accuracy by 10% to 45% for a number of the major types. The clinical features of the new entities were distinctive. Both the histologic types and the patient characteristics as defined by the International Prognostic Index predicted for patient survival. In conclusion we found that the ILSG classification can be readily applied and identifies clinically distinctive types of NHL. However, for clinical application, prognostic factors as defined by the International Prognostic Index must be combined with the histologic diagnosis for appropriate clinical decisions.

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Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression.

D S Basseres, A S Baldwin (2006)

Abundant data support a key role for the transcription factor nuclear factor-kappaB (NF-kappaB) signaling pathway in controlling the initiation and progression of human cancer. NF-kappaB and associated regulatory proteins such as IkappaB kinase (IKK) are activated downstream of many oncoproteins and there is much evidence for the activation of NF-kappaB-dependent target genes in a variety of solid tumors and hematologic malignancies. This review focuses on the mechanisms by which the NF-kappaB pathway is activated in cancer and on the oncogenic functions controlled by activated NF-kappaB. Additionally, the effects of NF-kappaB activation in tumors relative to cancer therapy are also discussed.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central

ISSN (Electronic): 1476-4598

Publication date Collection: 2010

Publication date (Electronic): 1 September 2010

Volume: 9

Page: 228

Affiliations

[1 ]Lymphoma Research Laboratory, Wayne State University - School of Med, 540 E. Canfield, 8229 Scott Hall, Detroit, MI 48201, USA

[2 ]Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA

[3 ]Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA

[4 ]Clinical Pathology, Wayne State University School of Medicine, 4727 St. Antoine, Detroit, MI 48201, USA

[5 ]Internal Medicine, Wayne State Univeristy, 2224 Ellimann Bldg, 421 E. Canfield, Detroit, MI 48201, USA

[6 ]Karmanos Cancer Institute, 732 HWCRC, 4100 John R, Detroit, MI 48201, USA

Article

Publisher ID: 1476-4598-9-228

DOI: 10.1186/1476-4598-9-228

PMC ID: 2940845

PubMed ID: 20809973

SO-VID: 50fd23a0-8b45-46cc-8acb-d8a7419f4a94

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

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Abstract

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Karger: Oncology

Most cited references 33

Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression.

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