Niclosamide Inhibits Cell Growth and Enhances Drug Sensitivity of Hepatocellular Carcinoma Cells via STAT3 Signaling Pathway

Wang, Chengzhi; Zhou, Xiaoqing; Xu, Hongjuan; Shi, Xiaqing; Zhao, Jinfeng; Yang, Manyi; Zhang, Lihua; Jin, Xin; Hu, Yu; Li, Xia; Xiao, Xiangcheng; Liao, Mingmei

doi:10.7150/jca.26948

Cited by 34 publications

(23 citation statements)

References 26 publications

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“…In agreement with the previous findings on the anti‐cancer activities of niclosamide [29–33], we demonstrate that niclosamide is active against esophageal cancer cells regardless of cellular origin, cell type, and genetic mutations ( Figure ). In addition, we show that niclosamide at low micromolar concentrations exhibits preferential inhibitory effects on esophageal cancer cells compared with normal immortalized esophageal epithelial and fibroblast cell lines ( Figure ), suggesting the safe therapeutic window of niclosamide in the treatment of esophageal cancer.…”

Section: Discussionsupporting

confidence: 92%

Targeting Wnt/β‐catenin by anthelmintic drug niclosamide overcomes paclitaxel resistance in esophageal cancer

Wei

Liu

Yuan

et al. 2020

Fundamemntal Clinical Pharma

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Esophageal cancer is an aggressive malignancy, and its current treatment strategies are plagued with high rates of recurrence. In this work, we demonstrate that niclosamide, an anthelmintic drug, is a potential sensitizing candidate for overcoming chemoresistance in esophageal cancer. Using a panel of esophageal cancer cell lines and normal cells, we show that niclosamide has anti‐esophageal cancer activity and is likely to be less effective against normal esophageal epithelial and fibroblast cells. The combination of niclosamide with paclitaxel results in much greater efficacy than paclitaxel alone, suggesting that niclosamide is active against esophageal cancer cells that are resistant to paclitaxel. This is further confirmed by our results that niclosamide is effective in inhibiting proliferation and inducing apoptosis in paclitaxel‐resistant esophageal cancer cells. In line with the findings obtained from in vitro cell culture system, niclosamide augments the in vivo efficacy of paclitaxel and significantly arrests paclitaxel‐resistant esophageal cancer growth without causing toxicity in mice. Mechanistically, we show that niclosamide decreases β‐catenin level and activity, and inhibits phosphorylation of STAT3 and mTORC1 substrate 70S6K. Stabilization of β‐catenin level by Wnt activator lithium chloride (LiCl) significantly abolishes the inhibitory effects of niclosamide in inhibiting proliferation and survival but not suppressing phosphorylation of STAT3 and 70S6K in paclitaxel‐resistant esophageal cancer cells, suggesting that niclosamide sensitizes esophageal cancer cell to paclitaxel mainly through inhibiting Wnt/β‐catenin. Our work demonstrates the efficacy of niclosamide and its underlying mechanism in paclitaxel‐resistant esophageal cancer. Our work emphasizes that Wnt/β‐catenin inhibition is a sensitizing strategy in esophageal cancer.

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Section: Discussionsupporting

confidence: 92%

Targeting Wnt/β‐catenin by anthelmintic drug niclosamide overcomes paclitaxel resistance in esophageal cancer

Wei

Liu

Yuan

et al. 2020

Fundamemntal Clinical Pharma

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“…In addition, STM attenuated inflammation via inhibiting JAK2/STAT3 signaling in adjuvant induced arthritis [23]. STAT3 is known to be activated to regulate cell survival and apoptosis in response to stress [24,25]. Therefore, STAT3 is another target of STM and its activity is inhibited by STM.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of differentially expressed genes in hepatocellular carcinoma cells exposed to Swertiamarin

et al. 2019

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Aim: To explore gene expression profiling in hepatocellular carcinoma (HCC) cells exposed to swertiamarin. Methods: Cell viability, apoptosis and invasion were examined in HepG2 cells after swertiamarin treatment. Tumor growth of SK-Hep-1 cells xenografted in nude mice was monitored after swertiamarin treatment. Total RNA was isolated from HepG2 cells treated with swertiamarin for microarray analysis. The data of microarray were analyzed by bioinformatics. Results: Swertiamarin treatment decreased the viability and invasion while increased the apoptosis of HepG2 cells, and significantly inhibited the growth of SK-Hep-1 cells xenografted in nude mice. Pathway and biological process analysis of differentially expressed genes (DEGs) in swertiamarin treated HepG2 cells showed that PI3k-Akt was the most significant regulated pathway. 47 targets of swertiamarin were predicted by CGBVS while 21 targets were predicted by 3NN. Notably, 8 targets were predicted as the targets of swertiamarin by both programs, including two prominent targets JUN and STAT3. A large range of DEGs induced by swertiamarin could be regulated by JUN and STAT3. Conclusion: Swertiamarin treatment led to significant changes in the expression of a variety of genes that modulate cell survival, cell cycle progression, apoptosis, and invasion. Moreover, most of these genes can be clustered into pathway networks such as PI3K, JUN, STAT3, which are predicted targets of swertiamarin. Further confirmation of these targets will reveal the anti-tumor mechanisms of swertiamarin and facilitate the development of swertiamarin as a novel agent for cancer prevention and treatment.

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“…In depth, such effects were associated with the induction of reactive oxygen species (ROS) and relied on the activation of PKR-like ER kinase (PERK) and ATF3 [ 37 ]. In another study, niclosamide (1–20 μM) was shown to impair proliferation and to induce apoptosis in multiple HCC cell lines (i.e., HepG2, QGY-7703 and SMMC-7721) by negatively affecting the phosphorylation/activity of the oncogenic transcription factor STAT3 [ 38 ]. In the same cells, niclosamide was also able to potentiate the cytotoxicity of the chemotherapeutic drug cisplatin [ 38 ].…”

Section: Anti-cancer Effects Of Anthelmintic Drugs In Malignanciesmentioning

confidence: 99%

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

Laudisi

Marônek

Grazia

et al. 2020

IJMS

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Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.

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Niclosamide Inhibits Cell Growth and Enhances Drug Sensitivity of Hepatocellular Carcinoma Cells via STAT3 Signaling Pathway

Cited by 34 publications

References 26 publications

Targeting Wnt/β‐catenin by anthelmintic drug niclosamide overcomes paclitaxel resistance in esophageal cancer

Targeting Wnt/β‐catenin by anthelmintic drug niclosamide overcomes paclitaxel resistance in esophageal cancer

Bioinformatics analysis of differentially expressed genes in hepatocellular carcinoma cells exposed to Swertiamarin

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

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