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

We 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.Chemotherapeutic 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.Renal cell carcinoma is the most common (85%) malignant tumour of the kidney. Although the disease can be cured by removal of the kidney in cases of localized disease, about 20% of patients have detectable metastatic disease at the time of diagnosis, and 20 - 40% of patients develop metastases following surgery. The 2 year survival of patients with metastatic disease is under 20% [1,2], reflecting the poor response of the disseminated tumour to chemo- or radiotherapy.This resistance is at least in part the result of a low sensitivity of the tumour cells to apoptosis induction by these agents. Chemotherapeutic drugs are generally recognized as inducers of mitochondrial apoptosis, and the efficiency of this process is a determinant of the drug response [3]. Mitochondrial apoptosis is largely regulated by the Bcl-2 family of proteins [4]. This family contains both pro- and anti-apoptotic members. Apoptosis is initiated by one or several proteins from the BH3-only subgro