Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

Molecular Cancer

Research

Niko Zantl¹  Robert Besch²  Henry Zall³  Georg Häcker⁴  Arnim Weber⁴ 

[1] Clinic of Urology, Clinic Konstanz, Luisenstr, Konstanz, Germany;Department of Dermatology and Allergology, Ludwig-Maximilian University, Frauenlobstr, Munich, Germany;Institute for Medical Microbiology, Technische Universität München, Trogerstr, Munich, Germany;Institute of Medical Microbiology and Hygiene, University Freiburg, Hermann-Herder-Str, Freiburg, Germany;

关键词: Paclitaxel;    Renal Cell Carcinoma;    Etoposide;    Chemotherapeutic Drug;    Vinblastine;   

DOI  :  10.1186/1476-4598-9-164

 received in 2010-01-12, accepted in 2010-06-24,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundHuman renal cell carcinoma (RCC) is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models.ResultsWe here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c.ConclusionsChemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

【 授权许可】

Unknown   
© Zall et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. 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.