Journal of the National Cancer Institute Advance Access originally published online on June 10, 2008
JNCI Journal of the National Cancer Institute 2008 100(12):862-875; doi:10.1093/jnci/djn174
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© The Author 2008. Published by Oxford University Press.
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KINK-1, a Novel Small-Molecule Inhibitor of IKKβ, and the Susceptibility of Melanoma Cells to Antitumoral Treatment
Affiliations of authors: Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine (MS, BGW, HS, KA, TS, MPS), Department of Dermatology (MS, BGW, HS, KA, TS, MPS), and Interdisciplinary Collaborative Clinical Research Center (SK), University of Würzburg, Würzburg, Germany; Department of Dermatology and Venereology, University of Göttingen, Göttingen, Germany (MS, BGW, MPS); BayerHealthCare, Global Drug Discovery, Wuppertal, Germany (VV, OW, KZ)
Correspondence to: Michael P. Schön, MD, Department of Dermatology and Venereology, University Medical Center Göttingen, von-Siebold-Str 3, 37075 Göttingen, Germany (e-mail: michael.schoen{at}med.uni-goettingen.de).
Background: Increasing the efficacy of chemotherapeutics by reducing chemoresistance may be a useful strategy in cancer therapy. Constitutive activation of nuclear factor-kappa B (NF-
B) is a hallmark of various cancers, including melanoma, which is almost universally resistant to chemotherapy. NF-B is regulated by inhibitory B (IB) proteins, which are in turn phosphorylated by the IB kinase (IKK) complex.
Methods: The effect on NF-B activity of a novel small-molecule inhibitor of the β subunit of IKK (KINK-1; kinase inhibitor of nuclear factor-B-1) was assessed by measuring phosphorylation of the 
subunit of IB by immunoblotting, DNA binding by electrophoretic mobility shift assays, and nuclear translocation of NF-B using immunofluorescence. Regulation of NF-B–dependent gene expression was determined by microarray analysis, real-time and semiquantitative reverse transcription polymerase chain reaction (RT-PCR), and Western blot analyses. The effects of KINK-1 (alone and in combination with cytostatic agents) on melanoma cells were characterized by assessing proliferation, soft agar colony formation, and markers of apoptosis. The antitumoral efficacy of KINK-1 in combination with the cytostatic agents doxorubicin or camptothecin (all injected intraperitoneally) was tested in vivo by measuring lung weight and counting metastases in C57BL6 mice (groups of six) bearing metastases of melanoma cells. All statistical tests were two-sided.
Results: KINK-1 strongly suppressed both constitutive and induced NF-B activity in melanoma cells. It reduced the expression of NF-B–dependent gene products that regulate proliferation, cytokine production, and antiapoptotic responses but exhibited little antiproliferative or proapoptotic activity at the cellular level. However, KINK-1 markedly increased the activities of some cytostatic agents in vitro and abrogated doxorubicin-induced NF-B activation. Combined treatment of C57BL6 mice that had been injected with melanoma cells with KINK-1 and doxorubicin or camptothecin reduced metastases and pulmonary tumor mass compared with either treatment alone (mean lung weight 19 days after injection of melanoma cells of mice treated with 3 mg/kg KINK-1 alone, 1 mg/kg doxorubicin alone, and 1 mg/kg doxorubicin plus 3 mg/kg KINK-1 = 260 mg, 95% confidence interval (CI) = 216 to 305 mg; 268 mg, 95% CI = 224 to 313 mg; and 181 mg, 95% CI = 171 to 192 mg, respectively, P < .001 from t tests comparing mean lung weight of double-treated mice to that in mice treated with either compound alone).
Conclusion: Inhibition of constitutive and induced IKKβ-activity through treatment with KINK-1 might increase tumor susceptibility to chemotherapy.
| CONTEXT AND CAVEATS Prior knowledge
Constitutive activation of nuclear factor-kappa B (NF- Study design
The effects of KINK-1, a small molecule that inhibits NF- Contribution
The study suggested that inhibition of NF- Implications
Using agents that specifically prevent NF- Limitations The study did not address whether the inhibitor would be effective with oral administration, and in vivo data were confined to a single murine model of tumorigenesis that may not be applicable to human cancers.
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Manuscript received November 6, 2007; revised April 30, 2008; accepted May 2, 2008.
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J Natl Cancer Inst 2008 100: 833-835.
J Natl Cancer Inst 2008 100: 829.
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  S. J. Moschos, P. M. Chaudhary, and J. M. Kirkwood Resolving "Kinks" of Chemotherapy in Melanoma J Natl Cancer Inst, June 18, 2008; 100(12): 833 - 835. [Full Text] [PDF]
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