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Cryptotanshinone sensitizes Arsenic trioxide-induced Bel-7404 liver cancer cell apoptosis by downregulating phosphorylated-STAT3 in vitro and in vivo
Li Shen 1,Guangshun Zhang 2 #,Zhaohuan Lou 1,Guanhua Xu 3,Guangji Zhang 4 *
1.College of Basic Medical Science of Zhejiang Chinese Medicine University
2. Center for post-doctoral studies of China Academy of Chinese Medicine Science
3.Institute of Pharmacology of Zhejiang Chinese Medicine University,
4.First People's Hospital of Xiaoshan District
*Correspondence author
#Submitted by
Subject:
Funding: Specialized Research Fund for the Doctoral Program of Higher Education(No.No.20123322110001), Zhejiang province science and technology key projects (No.No.2012C13017-1)
Opened online: 1 June 2016
Accepted by: none
Citation: Li Shen,Guangshun Zhang,Zhaohuan Lou.Cryptotanshinone sensitizes Arsenic trioxide-induced Bel-7404 liver cancer cell apoptosis by downregulating phosphorylated-STAT3 in vitro and in vivo[OL]. [ 1 June 2016] http://en.paper.edu.cn/en_releasepaper/content/4693550
 
 
Background: Arsenic trioxide (ATO) is approved for treating terminal-stage liver cancer in China. Cryptotanshinone (CT), a STAT3 inhibitor, has exhibited certain anti-tumor potency; however, the use of ATO with CT for treating liver cancer has not been reported. Here we try to elucidate how CT could sensitize ATO-induced liver cancer cell apoptosis and examine its correlation with STAT3 in vitro and in vivo. Methods: Cell viabilityof ATO combined with CT was assessed by MTT assay. Cell apoptosis induced by ATO combined with CT was detected by Annexin V/PI staining and apoptosis-related proteins were detected by western blotting. STAT3-related proteins were analysis by western blotting analysis and Immunofluorescence assays. Efficacy evaluation of ATO combined with CT on xenograft was carried in nude mice and related proteins were analysis by Immunohistochemistry assays. Results: First we evaluated cell vitality, and our data indicated that the ATO combined with CT showed obvious growth inhibition of Bel-7404 cells compared to ATO or CT alone. Next we found that ATO combined with CT induced cell apoptosis in Bel-7404 cells and upregulated the activation of apoptosis-related proteins cleaved-caspase-3, cleaved-caspase-9, and cleaved-poly(ADP-ribose) polymerase in a time-dependent manner. Next, we found that ATO combined with CT not only inhibited the constitutive levels of phosphorylated-JAK2 and phosphorylated-STAT3Tyr705 but did so in a time-dependent manner. We also found that ATO combined with CT reversed the upregulated expression of phosphorylated-STAT3Tyr705 stimulated by interleukin-6 and downregulated STAT3 direct target genes and the anti-apoptotic proteins Bcl-2, XIAP, and survivin but obviously upregulated the promoting apoptosis proteins Bax, Bak, and Mcl-1. In vivo studies showed that ATO combined with CT decreased tumor growth. Tumors from ATO combined with CT-treated mice showed decreased levels of phosphorylated-STAT3Tyr705 and the anti-apoptotic protein Bcl-2 but an increased level of pro-apoptotic protein Bax. Conclusions: Our study provides strong evidence of the anti-tumor growth potency of ATO combined with CT and that phosphorylated-STAT3 played a key role in ATO combined with CT-induced liver cancer cell apoptosis.
Keywords:Arsenic trioxide; cryptotanshinone; cell apoptosis; liver cancer
 
 
 

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