Bortezomib synergizes TRAIL-induced apoptosis in gastric cancer cells.
Background/Aims Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a newly identified biological agent has shown promising antitumor effects in a wide range of cancers. However, gastric cancer cells are less sensitive than other cancer cells to TRAIL-induced apoptosis.Here, we combined TRAIL with bortezomib, a proteasomal inhibitor to induce apoptosis in three gastric cancer cell lines.Methods After the cells were treated with TRAIL and/or bortezomib, the cell viability, apoptosis and cell cycle distribution were examined. The levels of death receptors and the mitochondrial membrane potential were also detected. The expression of apoptosis-associated proteins was determined by Western blot.Results Bortezomib at low concentration significantly(P<0.05) enhanced the cytotoxic effect of TRAIL by enhancing apoptosis as well as cell cycle arrest at G2/M phase. The enhancement of efficiency of TRAIL by bortezomib involved up-regulation of death receptor 4 and 5, as well as reduction of the mitochondrial membrane potential. Further study showed that combined treatment with TRAIL and bortezomib down-regulated anti-apoptotic protein cIAP-1, and over expression of cIAP-1 significantly(P\0.05) reduced the synergistic effect between TRAIL and bortezomib.Conclusions Bortezomib synergizes TRAIL-induced apoptosis in human gastric cancer cells. The synergistic effect between these two drugs is associated with up-regulation of death receptors and down-regulation of cIAP-1.The combination of TRAIL and bortezomib might be an effective regimen for the treatment of advanced gastric cancer.
Liu
Jing
J
Department of Medical Oncology, The First Hospital of China Medical University, 110001 Shenyang, People’s Republic of China. liujing_cmu@hotmail.com
Qu
Xiu-Juan
XJ
Xu
Ling
L
Zang
Ye
Y
Qu
Jing-Lei
JL
Hou
Ke-Zuo
KZ
Liu
Yun-Peng
YP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib
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