Abstract
BackgroundRhein 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.MethodsThe 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.ResultsApoptosis 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.ConclusionsRhein 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.
Highlights
Rhein is a lipophilic anthraquinone extensively found in medicinal herbs
Rhein suppresses constitutive signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation and induces apoptosis in pancreatic cancer cells Based on the important role of STAT3 in the process of acquisition of resistance to epidermal growth factor receptor (EGFR) inhibitors and the structural similarity of rhein with the four known inhibitors of STAT3, namely napabucasin, STA-21, LLL12 and LY5 [19], computer-aided molecular docking results showed that rhein may combine directly with the STAT3 protein and affect the phosphorylation of the Y705 active site (Fig. 1a)
Our results suggest that rhein has a promising potential to be used as a novel antitumor agent in cotreatment with EGFR inhibitors
Summary
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. Yang et al Journal of Experimental & Clinical Cancer Research (2019) 38:31 kinase B (AKT) and the Janus Kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways, leading to tumor development and metastasis [8, 9]. EGFR has become an attractive molecular target for cancer therapy, including PC. The EGFR inhibitor erlotinib (Tarceva, OSI Pharmaceuticals, Inc., Melville, NY, USA) is the US Food and Drug Administration (FDA) approved it in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic PC [13]
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