Basic Research
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 14, 2005; 11(14): 2136-2141
Published online Apr 14, 2005. doi: 10.3748/wjg.v11.i14.2136
Hepatic preconditioning of doxorubicin in stop-flow chemotherapy: NF-κB/IκB-α pathway and expression of HSP72
Hui Lu, Zheng-Gang Zhu, Xue-Xin Yao, Ren Zhao, Chao Yan, Yi Zhang, Bing-Ya Liu, Hao-Ran Yin, Yan-Zhen Lin
Hui Lu, Chao Yan, Yi Zhang, Bing-Ya Liu, Shanghai Institute of Digestive Surgery, Rujin Hospital, Shanghai Second Medical University, Shanghai 200025, China
Zheng-Gang Zhu, Xue-Xin Yao, Ren Zhao, Hao-Ran Yin, Yan-Zhen Lin, Department of General Surgery, Rujin Hospital, Shanghai Second Medical University, Shanghai 200025, China
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. Hui Lu, Shanghai Institute of Digestive Surgery, Rujin Hospital, Shanghai Second Medical University, No. 197, Ruijin Road II, Shanghai 200025, China. luhui75@yahoo.com.cn
Telephone: +86-21-64370045-611006
Received: March 15, 2004
Revised: March 16, 2004
Accepted: April 5, 2004
Published online: April 14, 2005
Abstract

AIM: To provide hepatic protection through administration of doxorubicin before stop-flow chemotherapy (SFC) and to investigate the expression of heat shock protein 72 (HSP72) and role of nuclear factor kappa B (NF-κB) in this effect.

METHODS: The hepatic preconditioning of doxorubicin was established in a porcine model by injection of doxorubicin (1 mg/kg) before SFC. The experimental animals were randomized into two groups: groups receiving doxorubicin (DOX) and normal saline (NS). Serial serum and tissue samples were taken from both groups to evaluate the protection of doxorubicin. Western blot and immuno-precipitation were applied to detect the expression of HSP72, NF-κB p65 protein, inhibitor κB-α (IκB-α) and phosphorylated IκB-α as well. The expression of tumor necrosis factor α (TNF-α) was estimated by semiquantitative RT-PCR. And the extent of the hepatic injury was estimated with the level of serum aminotransferases.

RESULTS: An abundance production of HSP72 in porcine liver was observed after 24 h of intravenous administration of doxorubicin, but without any change in the expression of NF-κB p65 subunit in cytoplasm. NF-κB p65 subunit accumulated in nuclei at the end of SFC and reached its highest level at 30 min after the restoration of the abdominal circulation and decreased gradually during the 6 h after SFC in NS group, while there was little change in DOX group. There was also a slight decrease of IκB-α at 30 min after the restoration of the abdominal circulation in NS group accompanying with the appearance of phosphorylated IκB-α. The expression of TNF-α was significantly higher in NS group than that in DOX group (average 1.40±0.17 vs 0.62±0.22, P<0.01) at serial time points after SFC. Serum ALT and AST levels of NS group were higher after 24 h than those of DOX group (93.2±7.8 IU/L vs 53.3±13.9 IU/L, 217.0±29.4 IU/L vs 155.0±15.6 IU/L for ALT and AST respectively, P<0.05) and after 48 h than those of DOX group (66.6±18.1 IU/L vs 43.3±16.7 IU/L, 174.4±21.3 IU/L vs 125.7±10.5 IU/L for ALT and AST respectively, P<0.05).

CONCLUSION: Doxorubicin renders the liver to be tolerant to the hepatic influence in SFC in a porcine model through the NF-κB/IκB-α pathway with the expression of HSP72.

Keywords: SFC; NF-κB