title: C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling.
abstract: Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP-activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1α downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling.
authors.affiliation: Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, No.91, Qianjin Road, Kunshan, Jiangsu 215300, China, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China, Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China, Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China, Department of Medical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing, Jiangsu 210009, China, Department of Thoracic Surgery and Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, No. 299, Qingyang Road, Wuxi, Jiangsu 214023, China and Department of Medical Oncology Center, Institute of Integrated Traditional and Western Medicine Affiliated to Nanjing Medical University, Nanjing 210029, China.
authors.forename: Min-Bin
authors.initials: MB
authors.lastname: Chen
authors.affiliation: The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, No.91, Qianjin Road, Kunshan, Jiangsu 215300, China, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China, Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China, Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China, Department of Medical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing, Jiangsu 210009, China, Department of Thoracic Surgery and Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, No. 299, Qingyang Road, Wuxi, Jiangsu 214023, China and Department of Medical Oncology Center, Institute of Integrated Traditional and Western Medicine Affiliated to Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China.
authors.forename: Bang-shun
authors.initials: BS
authors.lastname: He
authors.affiliation: Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Mu-Xin
authors.initials: MX
authors.lastname: Wei
authors.affiliation: Department of Medical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing, Jiangsu 210009, China, Department of Thoracic Surgery and.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, No. 299, Qingyang Road, Wuxi, Jiangsu 214023, China and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, No. 299, Qingyang Road, Wuxi, Jiangsu 214023, China and Department of Medical Oncology Center, Institute of Integrated Traditional and Western Medicine Affiliated to Nanjing Medical University, Nanjing 210029, China lphty1_1@163.com.
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D021983:Cyclophilins / Q000378:metabolism; D015536:Down-Regulation; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology*; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D055372:AMP-Activated Protein Kinases; D002518:Ceramides; D021983:Cyclophilins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; C497442:HIF1A protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D; C504327:N-(alpha-hydroxyoctadecanoyl)phytosphingosine