Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors by inhibiting STAT3 pathway

Journal of Experimental & Clinical Cancer Research

Guang Liang¹  Yanting Kang¹  Shichong Lin¹  Lingyuan Xu¹  Lehe Yang¹  Chengguang Zhao¹  Jifa Li²  Xiaoying Huang³  Xuanxuan Dai³  Youqun Xiang³ 

[1] Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University;Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University;Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou;

关键词: Rhein;    Pancreatic cancer;    STAT3;    EGFR;    Inhibitor;   

DOI  :  10.1186/s13046-018-1015-9

来源: DOAJ

【 摘 要 】

Abstract Background Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics. Methods The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis. Results Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants. Conclusions Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.

【 授权许可】

Unknown