title: The small-molecule IAP antagonist AT406 inhibits pancreatic cancer cells in vitro and in vivo.
abstract: In the present study, we tested the anti-pancreatic cancer activity by AT406, a small-molecule antagonist of IAP (inhibitor of apoptosis proteins). In established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells, treatment of AT406 significantly inhibited cell survival and proliferation. Yet, same AT406 treatment was non-cytotoxic to pancreatic epithelial HPDE6c7 cells. AT406 increased caspase-3/-9 activity and provoked apoptosis in the pancreatic cancer cells. Reversely, AT406' cytotoxicity in these cells was largely attenuated with pre-treatment of caspase inhibitors. AT406 treatment caused degradation of IAP family proteins (cIAP1 and XIAP) and release of cytochrome C, leaving Bcl-2 unaffected in pancreatic cancer cells. Bcl-2 inhibition (by ABT-737) or shRNA knockdown dramatically sensitized Panc-1 cells to AT406. In vivo, oral administration of AT406 at well-tolerated doses downregulated IAPs (cIAP1/XIAP) and inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) nude mice. Together, our preclinical results suggest that AT406 could be further evaluated as a promising anti-pancreatic cancer agent.
authors.affiliation: Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, No.9677 Jing-Shi Road, Jinan 250014, China. Electronic address: sunbaoyou_sdu@yeah.net.
authors.forename: Baoyou
authors.initials: B
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D001392:Azocines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001392:Azocines; D001559:Benzhydryl Compounds; 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
keywords: AT406; Apoptosis; Bcl-2; IAPs; Pancreatic cancer