Short-chain C6 ceramide sensitizes AT406-induced anti-pancreatic cancer cell activity

作者

Zhao, XG;Sun, BY;Zhang, JJ;Zhang, RS;Zhang, Q

作者单位

[Zhao, Xiaoguang] CPLA Bethune Int Peace Hosp, Dept Neurosurg, 398 Zhongshan West Rd, Shijiazhuang 050082, Hebei, Peoples R China.;-;[Sun, Baoyou] Shandong Univ, Shandong Prov Hosp, Dept Gen Surg, Jinan, Peoples R China.;-;[Zhang, Jingjing] Chest Hosp Hebei Prov, Dept Thorac Surg 3, Shijiazhuang, Hebei, Peoples R China.;-;[Zhang, Ruishen] Hosp China Railway Elect Bur Grp First Engn Co, Shijiazhuang, Hebei, Peoples R China.;-;[Zhang, Qing] Chest Hosp Hebei Prov, Dept Neurol, Shijiazhuang, Hebei, Peoples R China.

摘要

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 (Pant-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. (C) 2016 The Authors. Published by Elsevier Inc.

关键词

IN-VITRO; IAP PROTEINS; VIVO; CHEMOTHERAPY; INHIBITOR; APOPTOSIS; FAMILY; INTERVENTION; GEMCITABINE; SURVIVAL

基本信息

所属机构:

归属医师: 孙宝友

PMID：27562715

UT：000385898900008

刊名:BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

年，卷(期):2016年479卷2期

页码：166-172

DOI：10.1016/j.bbrc.2016.08.121

附件：

收录: SCIE