C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: A mechanism study

Here we reported that co-administration of docetaxel and a cell-permeable short-chain ceramide (C6) resulted in a striking increase in growth inhibition and apoptosis in primary and transformed breast cells (MCF-7 and MDA-231), which were associated with mitochondrial permeability transition pore (mPTP) opening, a significant reactive oxygen species (ROS) production and the pro-apoptotic AMP-Protein Kinase (AMPK) as well as c-Jun N-terminal kinases (JNK) activations. Contrarily, the mPTP blocker sanglifehrin A (SfA) or the ROS scavenger N-acetyl-l-cysteine (NAC) largely inhibited co-administration-induced cytotoxicity. Further, cyclosporin A (CsA), the inhibitor of cyclophilin-D (Cyp-D, the key mPTP component), as well as Cyp-D RNA silencing also suppressed breast cancer cell death by the co-treatment, while cells overexpressing Cyp-D showed hypersensitivity to docetaxel. Meanwhile, JNK and AMPK inhibition alleviated cell death induced by the co-administration in cultured breast cancer cells. Significantly, C6 ceramide plus docetaxel caused dramatic human epidermal growth factor receptor (HER)-1/-2 degradation and downstream Akt/Erk inhibition in HER-2 expressing MDA-231 cells. These in vitro findings provide confidence in support of further development of C6 ceramide as an adjunct of docetaxel for the treatment of the metastatic breast cancer.