title: C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study.
abstract: 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.
authors.affiliation: Department of Breast Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Li-Yun
authors.initials: LY
authors.lastname: Zheng
authors.affiliation: Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Dong
authors.affiliation: Department of Breast Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
authors.forename: Xu-Fen
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Cardiothoracic Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, China. Electronic address: dryangbosz@163.com.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: caocong@suda.edu.cn.
authors.forename: Cong
authors.initials: C
authors.lastname: Cao
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D059748:Proteolysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D006877:Hydroxamic Acids; D046912:Multiprotein Complexes; D043823:Taxoids; C101954:N-caproylsphingosine; D000077143:Docetaxel; D000077337:Vorinostat; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D000263:Adenylate Kinase; D017239:Paclitaxel; D002945:Cisplatin
keywords: C6 ceramide; Docetaxel; Metastatic breast cancer; Mitochondrial permeability transition pore; ROS; Signaling transduction