IκB kinase β inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells Journal Article
| Authors: | Duncan, E. A.; Goetz, C. A.; Stein, S. J.; Mayo, K. J.; Skaggs, B. J.; Ziegelbauer, K.; Sawyers, C. L.; Baldwin, A. S. |
| Article Title: | IκB kinase β inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells |
| Abstract: | Chronic myelogenous leukemia is a malignant disease of the hematopoietic stem cell compartment, which is characterized by expression of the BCR-ABL fusion protein. Expression of BCR-ABL allows myeloid cells to grow in the absence of the growth factors interleukin-3 and granulocyte-macrophage colony-stimulating factor. The tyrosine kinase activity of BCR-ABL constitutively activates signaling pathways associated with Ras and its downstream effectors and with the Jak/STAT pathway. Additionally, we reported previously that BCR-ABL activates the transcription factor nuclear factor-κB (NF-κB) in a manner dependent on Ras and that inhibition of NF-κB by expression of a modified form of IκBα blocked BCRABL-driven tumor growth in a xenograft model. Here, we show that a highly specific inhibitor of IκB kinase β, a key upstream regulator of the NF-κB pathway, induces growth suppression and death in cells expressing wild-type, Imatinib-resistant, or the T315I Imatinib/Dasatinib-resistant forms of BCR-ABL. Cell cycle variables were not affected by this compound. These data indicate that blockage of BCR-ABL-induced NF-κB activation via IκB kinase β inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia. Copyright © 2008 American Association for Cancer Research. |
| Keywords: | nonhuman; antineoplastic agents; antineoplastic agent; animal cell; mouse; metabolism; cell death; cell survival; cell cycle; imatinib; drug inhibition; protein kinase inhibitor; animal experiment; animal model; immunoglobulin enhancer binding protein; drug effect; drug resistance; drug screening; drug resistance, neoplasm; tumor cells, cultured; drug evaluation, preclinical; transfection; dasatinib; chronic myeloid leukemia; pyrimidines; phosphorylation; wild type; physiology; protein kinase inhibitors; oncogene; drug antagonism; genetic transfection; cell culture; i kappa b kinase beta; bcr abl protein; piperazines; piperazine derivative; pyrimidine derivative; thiazoles; i kappa b kinase; growth inhibition; thiazole derivative; i-kappa b kinase; genes, abl |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 7 |
| Issue: | 2 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-02-01 |
| Start Page: | 391 |
| End Page: | 397 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-07-0305 |
| PUBMED: | 18245668 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 9" - "Export Date: 17 November 2011" - "CODEN: MCTOC" - "Source: Scopus" |
