L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway

Bai, Encheng; Yang, Lehe; Xiang, Youqun; Hu, Wanle; Li, Caleb; Lin, Jiayuh; Dai, Xuanxuan; Liang, Guang; Jin, Rong; Zhao, Chengguang

doi:10.2147/cmar.s159090

Cited by 14 publications

(10 citation statements)

References 41 publications

(49 reference statements)

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“…Based on the important role of STAT3 in the process of NSCLC and the structural similarity of Rhein with the four known inhibitors of STAT3 (Napabucasin, STA-21, LLL12 and LY5), we thought that Rhein may affect the phosphorylation of STAT3 11,21. We tested the inhibiting ability of Rhein on STAT3 phosphorylation (P-STAT3) in NSCLC cells.…”

Section: Resultsmentioning

confidence: 99%

Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway

Yang¹,

Li²,

Xu³

et al. 2019

CMAR

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Background: Non-small-cell lung cancer (NSCLC) comprises about 85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. The IL-6/STAT3 signaling pathway plays a pivotal role in NSCLC biology. Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that Rhein has significant antitumor effects, supporting the potential uses of Rhein as an antitumor agent. Methods: Cell viability and colony formation were performed to examine Rhein's potent antiproliferative effect in human NSCLC cell lines PC-9, H460 and A549. Flow cytometry-based assay was employed to study whether Rhein could affect cell apoptosis and cycle. The expression level of P-STAT3, apoptosis and cycle-related proteins Bcl-2, Bax, MDM2, CDC2, P53 and CyclinB1 were detected by Western blotting. The xenograft models were used to evaluate the in vivo effect of Rhein. Results: We found that Rhein could significantly reduce the viability and stimulate apoptosis in human NSCLC cells in a dose-dependent manner. Western blot analysis results suggested that the antitumor effect of Rhein might be mediated via STAT3 inhibition. Rhein upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. In addition, Rhein induced the arrest of NSCLC cells in the G2/M phase of the cell cycle and dose dependently inhibited the expression of cycle-related proteins. The Rhein also inhibited tumor growth in H460 xenograft models. Conclusion: Rhein shows potent efficacy against NSCLC through inhibiting the STAT3 pathway. Our results also suggest that Rhein has a promising potential to be used as a novel antitumor agent for the treatment of NSCLC.

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Section: Resultsmentioning

confidence: 99%

Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway

Yang¹,

Li²,

Xu³

et al. 2019

CMAR

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“…Inhibition of STAT3 using small molecules or RNAi reduced cancer cell proliferation, migration and invasion, and induced apoptosis in vitro [179,[255][256][257], whilst reducing tumour growth and angiogenesis in vivo [256,258]. Liposomal delivery of a small molecule STAT3 inhibitor reduced STAT3 activation and cell growth, and sensitised cells to radiotherapy and chemotherapy in vitro and in vivo [240].…”

Section: Do Il-6 Family Cytokines Represent a New Therapeutic Opportumentioning

confidence: 99%

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

2020

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Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.

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“…An increasing number of studies have shown that abnormal activation of STAT3 occurs in a variety of drug-resistant cells, and inhibition of STAT3 can reverse drug resistance 17. Therefore, STAT3 is deemed as an attractive target for antitumor drug development 21,22…”

Section: Discussionmentioning

confidence: 99%

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

Zhuang¹,

Bai²,

Hu³

et al. 2019

OTT

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Background Activation of epidermal growth factor receptor (EGFR) has been reported in a variety of cancer types, including colorectal cancer (CRC), and represents a potential chemotherapeutic drug target. EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been increasingly applied in the clinical treatment of CRC, but development of drug resistance during the treatment has greatly limited their application. Signal transducer and activator of transcription 3 (STAT3) and its mediated signal transduction pathway play an important role in the occurrence, development and metastasis of CRC, and are related to the development of EGFR-TKI resistance in CRC. Methods Cell viability, colony formation and cellular morphology were examined to evaluate the potent antiproliferative effect of the STAT3 inhibitor napabucasin, LY5 and rhein on the human CRC cell lines HCT116, SW620, RKO and DLD-1. Flow cytometry-based analysis was employed to determine whether rhein can affect the cell cycle and apoptosis. The expression level of phosphorylated STAT3 (P-STAT3), and cell cycle- and apoptosis-related proteins BCL2, CDC2 BAX, Cyclin D1 and Cyclin B1 were detected by Western blot analysis. Results This study revealed that rhein can significantly reduce cell viability and stimulate apoptosis in human CRC cells in a dose-dependent manner. In addition, rhein induced cell cycle arrest at the G2/M phase in CRC cells and dose-dependently inhibited the expression of cell cycle-related proteins. Additionally, it was found that napabucasin, LY5 and rhein considerably sensitized cells to the EGFR-TKI erlotinib, thus suppressing CRC cell proliferation. Rhein also inhibited the phosphorylation of its downstream target STAT3. Inhibition of STAT3 and EGFR phosphorylation was also observed after treatment with a combination of rhein and EGFR inhibitors. Conclusion This study confirmed the synergistic effect of STAT3 inhibitor and EGFR inhibitor in CRC cell lines. Additionally, we found that rhein sensitizes human CRC cells to EGFR-TKIs by inhibiting STAT3 pathway. When combined with EGFR-TKIs, rhein may be a novel STAT3 inhibitor in CRC.

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L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway

Cited by 14 publications

References 41 publications

<p>Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway</p>

<p>Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway</p>

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

<p>Rhein sensitizes human colorectal cancer cells to EGFR inhibitors by inhibiting STAT3 pathway</p>

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