I-kappa-kinase-2 (IKK-2) Inhibition Potentiates Vincristine Cytotoxicity in Non-Hodgkin's Lymphoma

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2010 Sep 3

PMID 20809973

Citations 11

Authors

Ayad Al-Katib

Alan A Arnold

Amro Aboukameel

Angela Sosin

Peter Smith

Anwar N Mohamed

Frances W Beck

Ramzi M Mohammad

Affiliations

Soon will be listed here.

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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References

Mayo M, Baldwin A . The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta. 2000; 1470(2):M55-62. DOI: 10.1016/s0304-419x(00)00002-0. View

Mohammad R, Al-Katib A, Aboukameel A, Doerge D, Sarkar F, Kucuk O . Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Mol Cancer Ther. 2004; 2(12):1361-8. View

Young G, Iland H . Clinical perspectives in lymphoma. Intern Med J. 2007; 37(7):478-84. DOI: 10.1111/j.1445-5994.2007.01402.x. View

Heckman C, Mehew J, Boxer L . NF-kappaB activates Bcl-2 expression in t(14;18) lymphoma cells. Oncogene. 2002; 21(24):3898-908. DOI: 10.1038/sj.onc.1205483. View

Huang Y, Fang Y, Wu J, Dziadyk J, Zhu X, Sui M . Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells. Mol Cancer Ther. 2004; 3(3):271-7. View

Hideshima T, Neri P, Tassone P, Yasui H, Ishitsuka K, Raje N . MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res. 2006; 12(19):5887-94. DOI: 10.1158/1078-0432.CCR-05-2501. View

Wuerzberger-Davis S, Chang P, Berchtold C, Miyamoto S . Enhanced G2-M arrest by nuclear factor-{kappa}B-dependent p21waf1/cip1 induction. Mol Cancer Res. 2005; 3(6):345-53. DOI: 10.1158/1541-7786.MCR-05-0028. View

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

Karin M, Yamamoto Y, Wang Q . The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov. 2004; 3(1):17-26. DOI: 10.1038/nrd1279. View

10.

Bernal-Mizrachi L, Lovly C, Ratner L . The role of NF-{kappa}B-1 and NF-{kappa}B-2-mediated resistance to apoptosis in lymphomas. Proc Natl Acad Sci U S A. 2006; 103(24):9220-5. PMC: 1482593. DOI: 10.1073/pnas.0507809103. View

11.

Duan H, Heckman C, Boxer L . The immunoglobulin heavy-chain gene 3' enhancers deregulate bcl-2 promoter usage in t(14;18) lymphoma cells. Oncogene. 2006; 26(18):2635-41. DOI: 10.1038/sj.onc.1210061. View

12.

Karin M . Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6. DOI: 10.1038/nature04870. View

13.

Chen X, Kandasamy K, Srivastava R . Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 2003; 63(5):1059-66. View

14.

Shinwari Z, Manogaran P, Alrokayan S, Al-Hussein K, Aboussekhra A . Vincristine and lomustine induce apoptosis and p21(WAF1) up-regulation in medulloblastoma and normal human epithelial and fibroblast cells. J Neurooncol. 2007; 87(2):123-32. DOI: 10.1007/s11060-007-9502-4. View

15.

Mohammad R, Abubakr Y, Dan M, Aboukameel A, Chow C, Mohamed A . Bcl-2 antisense oligonucleotides are effective against systemic but not central nervous system disease in severe combined immunodeficient mice bearing human t(14;18) follicular lymphoma. Clin Cancer Res. 2002; 8(4):1277-83. View

16.

Mohammad R, Mohamed A, Smith M, Jawadi N, Al-Katib A . A unique EBV-negative low-grade lymphoma line (WSU-FSCCL) exhibiting both t(14;18) and t(8;11). Cancer Genet Cytogenet. 1993; 70(1):62-7. DOI: 10.1016/0165-4608(93)90132-6. View

17.

Bharti A, Donato N, Singh S, Aggarwal B . Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood. 2002; 101(3):1053-62. DOI: 10.1182/blood-2002-05-1320. View

18.

Wang L, MacDonald R . Effects of microtubule-depolymerizing agents on the transfection of cultured vascular smooth muscle cells: enhanced expression with free drug and especially with drug-gene lipoplexes. Mol Ther. 2004; 9(5):729-37. DOI: 10.1016/j.ymthe.2004.02.009. View

19.

Wen D, Nong Y, Morgan J, Gangurde P, Bielecki A, Dasilva J . A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells. J Pharmacol Exp Ther. 2006; 317(3):989-1001. DOI: 10.1124/jpet.105.097584. View

20.

Heckman C, Cao T, Somsouk L, Duan H, Mehew J, Zhang C . Critical elements of the immunoglobulin heavy chain gene enhancers for deregulated expression of bcl-2. Cancer Res. 2003; 63(20):6666-73. View