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

Background: Human renal cell carcinoma (RCC) is very resistant to
chemotherapy. ABT-737 is a novel inhibitor of antiapoptotic
proteins of the Bcl-2 family that has shown promise in various
preclinical tumour models. Results: 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.
Conclusions: 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.