The small-molecule IAP antagonist AT406 inhibits pancreatic cancer cells in vitro and in vivo

作者

Jiang, YS;Meng, QH;Chen, B;Shen, HY;Yan, B;Sun, BY

作者单位

[Jiang, Yongsheng; Meng, Qinghua; Shen, Haiyu; Yan, Bing] Shandong Univ, Jinan Cent Hosp, Dept Gen Surg, Jinan, Peoples R China.;-;[Chen, Bo] Tongji Univ Shanghai, East Hosp, Dept Biliary & Pancreat Surg, Shanghai, Peoples R China.;-;[Sun, Baoyou] Shandong Univ, Shandong Prov Hosp, Dept Gen Surg, 9677 Jing Shi Rd, Jinan 250014, Peoples R China.

摘要

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 down regulated 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. (C) 2016 Elsevier Inc. All rights reserved.

关键词

INDUCED APOPTOSIS; PROTEINS; FAMILY; INTERVENTION; CHEMOTHERAPY; GEMCITABINE; TARGETS

基本信息

所属机构:

归属医师: 孙宝友

PMID：27387230

UT：000381332800045

刊名:BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

年，卷(期):2016年478卷1期

页码：293-299

DOI：10.1016/j.bbrc.2016.07.011

附件：

收录: SCIE