title: Short-chain C6 ceramide sensitizes AT406-induced anti-pancreatic cancer cell activity.
abstract: Our previous study has shown that AT406, a first-in-class small molecular antagonist of IAPs (inhibitor of apoptosis proteins), inhibits pancreatic cancer cell proliferation in vitro and in vivo. The aim of this research is to increase AT406's sensitivity by adding short-chain C6 ceramide. We show that co-treatment of C6 ceramide dramatically potentiated AT406-induced caspase/apoptosis activation and cytotoxicity in established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells. Reversely, caspase inhibitors largely attenuated C6 ceramide plus AT406-induced above cancer cell death. Molecularly, C6 ceramide downregulated Bcl-2 to increase AT406's sensitivity in pancreatic cancer cells. Intriguingly, C6 ceramide-mediated AT406 sensitization was nullified with Bcl-2 shRNA knockdown or pretreatment of the Bcl-2 inhibitor ABT-737. In vivo, liposomal C6 ceramide plus AT406 co-administration dramatically inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) mice. The combined anti-tumor activity was significantly more potent than either single treatment. Expressions of IAPs (cIAP1/XIAP) and Bcl-2 were downregulated in Panc-1 xenografts with the co-administration. Together, we demonstrate that C6 ceramide sensitizes AT406-mediated anti-pancreatic cancer cell activity possibly via downregulating Bcl-2.
authors: Department of Neurosurgery, CPLA Bethune International Peace Hospital, Shijiazhuang, Hebei, China. Electronic address: zhaoxiaoguang7972@126.com.
authors: Xiaoguang
authors: X
authors: Zhao
authors: Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors: Baoyou
authors: B
authors: Sun
authors: Department of Thoracic Surgery III, The Chest Hospital of Hebei Province, Shijiazhuang, Hebei, China.
authors: Jingjing
authors: J
authors: Zhang
authors: Hospital of China Railway Electric Bureau Group First Engineering Company, Shijiazhuang, Hebei, China.
authors: Ruishen
authors: R
authors: Zhang
authors: Department of Neurology, The Chest Hospital of Hebei Province, Shijiazhuang, Hebei, China.
authors: Qing
authors: Q
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001392:Azocines / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D009596:Nitrophenols / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001392:Azocines; D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds; D002518:Ceramides; D051034:Inhibitor of Apoptosis Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides
keywords: AT406; Bcl-2; C6 ceramide; IAPs; Pancreatic cancer