HJC0152, a novel STAT3 inhibitor with promising anti-tumor effect in gastric cancer

Jiang, Xiaoxia; Wu, Mengjie; Xu, Zhenzhen; Wang, Haohao; Yu, Xiaofei; Li, Zhongqi; Teng, Lisong

doi:10.2147/cmar.s188364

Cited by 21 publications

(9 citation statements)

References 38 publications

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“…The signal transducer and activator of transcription protein (STAT), belongs to the family of cytoplasmic transcription factors, has been demonstrated played signi cant role in the signal transduction through multiple mechanisms [13]. Increasing evidences revealed that the STAT3 was involved in the development and progression of many cancer types through participation in a series of tumorigenic processes such as cell proliferation and survival [14]. Moreover, aberrant expression and constitutive activation of STAT3 have been detected in a variety of tumors such as the gastric cancer, breast cancer, prostate tumor, and NSCLC [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Increasing evidences revealed that the STAT3 was involved in the development and progression of many cancer types through participation in a series of tumorigenic processes such as cell proliferation and survival [14]. Moreover, aberrant expression and constitutive activation of STAT3 have been detected in a variety of tumors such as the gastric cancer, breast cancer, prostate tumor, and NSCLC [13][14][15]. Additionally, knockdown of STAT3 was proved to be facilitate to enhance the chemotherapy e cacy of malignant cancer by inhibition cell proliferation, invasion, and inhibition of drug-resistance [16].…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: PYCR1 Promotes Proliferation, Invasion and Drug-Resistance of Lung Cancer Cells by Regulating STAT3-Mediated PI3K/AKT and NF-κB Signaling Pathway

Yu¹,

Wang²,

Zhang³

et al. 2020

Preprint

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Abstract Background: Aberrant expression of PYCR1 has been proved to be one of the most pivotal regulators of tumor progress and metastasis. However, the detailed role of PYCR1 in promotion of NSCLC progress is not investigated thoroughly. The present study was aimed to thoroughly investigate the effect of PYCR1 in the growth of NSCLC and the underlying mechanisms, so that provide valuable theoretical basis for efficient treatment of NSCLC. Methods: The expressions of PYCR1 and its target genes and downstream signals were respectively determined by Western-blot assay and RT-qPCR experiment. Cell growth of NSCLC cells was investigated using the CCK-8 kit while the proliferation assay was performed with the help of EDU staining. The NSCLC-bearing mice mode was established to evaluate the effect of PYCR1 on the progress of NSCLC and the underlying mechanisms in vivo.Results: It was firstly demonstrated that the PYCR1 was overexpressed in lung cancer tissues and cells and overexpression of PYCR1 contributed to significantly enhanced proliferation, invasion, and drug-resistance of cancer cells and progress of NSCLC tissues. Further studies revealed that up-regulation of PYCR1 level resulted to the elevation of bioactivity of STAT3. Additionally, the positive correlation between the expression of PYCR1 and STAT3 indicated that the PYCR1 promotes the growth of NSCLC through targeting regulation the STAT3 levels. Furthermore, activation of STAT3 by PYCR1 was proved to be able of awaking the PI3K/AKT and NF-κB signaling pathway, which was extremely important to the metabolism, proliferation, cell survival, and growth of many cancer cell types.Conclusion: In conclusion, our study demonstrated that PYCR1 was specifically overexpressed in lung cancer and closely related to rapid progress and drug-resistance thorough regulating the STAT3-mediated PI3K/AKT and NF-κB signaling pathway. It may provide a valuable strategy for treatment of malignant lung cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: PYCR1 Promotes Proliferation, Invasion and Drug-Resistance of Lung Cancer Cells by Regulating STAT3-Mediated PI3K/AKT and NF-κB Signaling Pathway

Yu¹,

Wang²,

Zhang³

et al. 2020

Preprint

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“…Our previous studies and a report from other groups have shown that STAT3 is a primary target of HJC0152 in breast cancer, head and neck squamous cell carcinoma, glioma, and gastric cancer . In this study, we showed that STAT3 expression is a prognostic factor for NSCLC patients (Figure A‐C), and that STAT3 is activated in NSCLC cells (Figure D and E).…”

Section: Resultssupporting

confidence: 74%

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

et al. 2020

Cell Proliferation

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Objectives Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non–small‐cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC. Materials and methods We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC‐QTOF/MS was used for untargeted metabolomic relative quantitation analysis. Results We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways. Conclusions HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti‐cancer effects.

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“…Interestingly, STA-21 slightly but significantly reduced ERK activity in MOLT-4 cells. It was recently reported that STAT3 inhibitor HJC0152 affected ERK activity in gastric cancer cells (20). Moreover, we found that STA-21 alone had no effect on levels of total and phosphorylated STAT3 protein in either cell line.…”

Section: Discussionsupporting

confidence: 44%

Combination of ERK2 and STAT3 Inhibitors Promotes Anticancer Effects on Acute Lymphoblastic Leukemia Cells

Jasek-Gajda

Jurkowska

Jasińska

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Deregulated activation of signaling through the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/RAF/MEK/ ERK) and signal transducer and activator of transcription (STAT) pathways is involved in numerous hematological malignancies, making it an attractive therapeutic target. This study aimed to assess the effect of the combination of ERK2 inhibitor VX-11e and STAT3 inhibitor STA-21 on acute lymphoblastic leukemia cell lines REH and MOLT-4. Materials and Methods: REH and MOLT-4 cell lines were cultured with each drug alone and in combination. Cell viability, ERK activity, cell cycle distribution, apoptosis and oxidative stress induction were assessed by flow cytometry. Protein levels of STAT3, phospho-STAT3, protein tyrosine phosphatase 4A3 (PTP4A3), survivin, p53 and p21 were determined by western blotting. Results: VX-11e in combination with STA-21 significantly inhibited cell viability, induced G 0 /G 1 cell-cycle arrest, enhanced production of reactive oxygen species, and induced apoptosis. These effects were associated with an increased level of p21 protein in REH cells and with reduced levels of phopho-STAT3, survivin and PTP4A3 proteins in MOLT-4 cells. Conclusion: Our findings provide a rationale for combined inhibition of RAS/RAF/MEK/ERK and STAT3 pathways in order to enhance anticancer effects against acute lymphoblastic leukemia cells.

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HJC0152, a novel STAT3 inhibitor with promising anti-tumor effect in gastric cancer

Cited by 21 publications

References 38 publications

WITHDRAWN: PYCR1 Promotes Proliferation, Invasion and Drug-Resistance of Lung Cancer Cells by Regulating STAT3-Mediated PI3K/AKT and NF-κB Signaling Pathway

WITHDRAWN: PYCR1 Promotes Proliferation, Invasion and Drug-Resistance of Lung Cancer Cells by Regulating STAT3-Mediated PI3K/AKT and NF-κB Signaling Pathway

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

Combination of ERK2 and STAT3 Inhibitors Promotes Anticancer Effects on Acute Lymphoblastic Leukemia Cells

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