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Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity.
Hussain, Syed-Rehan A; Cheney, Carolyn M; Johnson, Amy J; Lin, Thomas S; Grever, Michael R; Caligiuri, Michael A; Lucas, David M; Byrd, John C.
Afiliação
  • Hussain SR; Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Clin Cancer Res ; 13(7): 2144-50, 2007 Apr 01.
Article em En | MEDLINE | ID: mdl-17404098
PURPOSE: The antiapoptotic Bcl-2 family member protein Mcl-1 is dynamically regulated in transformed B-cells, has a short mRNA and protein half-life, and is rapidly processed during apoptosis. Multiple therapies cause down-regulation of Mcl-1 in chronic and acute lymphoid leukemia (CLL and ALL) cells. Mcl-1 has also been reported to mediate resistance to rituximab in CLL. We therefore investigated whether direct reduction of Mcl-1 was sufficient to induce apoptosis and increase sensitivity to rituximab. EXPERIMENTAL DESIGN: We used Mcl-1-specific small interfering RNA in ALL cell lines and tumor cells from CLL patients to block transcription of Mcl-1. RESULTS: We show that Mcl-1 down-regulation alone is sufficient to promote mitochondrial membrane depolarization and apoptosis in ALL and CLL cells. Given the importance of rituximab in B-cell malignancies, we next assessed the influence of Mcl-1 down-regulation on antibody-mediated killing. Mcl-1 down-regulation by small interfering RNA increased sensitivity to rituximab-mediated killing both by direct apoptosis and complement-dependent cytotoxicity, but did not enhance antibody-dependent cellular cytotoxicity. CONCLUSIONS: These results show that Mcl-1 is a relevant therapeutic target for ALL and CLL, and its down-regulation has the potential to enhance the therapeutic effect of rituximab in CD20-bearing lymphoid cells.
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Base de dados: MEDLINE Assunto principal: Leucemia Linfoide / Apoptose / Proteínas Proto-Oncogênicas c-bcl-2 / Citotoxicidade Imunológica / Anticorpos Monoclonais / Proteínas de Neoplasias / Antineoplásicos Idioma: En Ano de publicação: 2007 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Leucemia Linfoide / Apoptose / Proteínas Proto-Oncogênicas c-bcl-2 / Citotoxicidade Imunológica / Anticorpos Monoclonais / Proteínas de Neoplasias / Antineoplásicos Idioma: En Ano de publicação: 2007 Tipo de documento: Article