Format

Send to

Choose Destination
BMC Complement Altern Med. 2017 Feb 10;17(1):106. doi: 10.1186/s12906-016-1548-4.

Cryptotanshinone enhances the effect of Arsenic trioxide in treating liver cancer cell by inducing apoptosis through downregulating phosphorylated- STAT3 in vitro and in vivo.

Author information

1
College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Bin Wen Road, Hangzhou, 310053, Zhejiang Province, China.
2
Center for post-doctoral studies, China Academy of Chinese Medicine Science, Beijing, China.
3
College of pharmacy, Zhejiang Chinese Medicine University, Hang Zhou, People's Republic of China.
4
Institute of Pharmacology, Zhejiang Chinese Medicine University, Hang Zhou, People's Republic of China.
5
First People's Hospital of Xiaoshan District in Hangzhou, Hang Zhou, China.
6
College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Bin Wen Road, Hangzhou, 310053, Zhejiang Province, China. zgj@zcmu.edu.cn.

Abstract

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 CT enhanced ATO for treating liver cancer has not been reported. Here we try to elucidate how CT could enhance the efficacy of ATO for treating liver cancer and its correlation to STAT3 in vitro and in vivo.

METHODS:

Cell viability of ATO combined with CT was assessed by 1MTT 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 Bak,.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 that CT could enhance the efficacy of ATO in treating liver cancer both in vitro and in vivo. Downregulation of phosphorylated-STAT3 expression may play an important role in inducing apoptosis of Bel-7404 cells.

KEYWORDS:

Arsenic trioxide; Cell apoptosis; Cryptotanshinone; Liver cancer

PMID:
28187727
PMCID:
PMC5303285
DOI:
10.1186/s12906-016-1548-4
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center