Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model

Chulwon, Kim; Lee, Seok‐Geun; Yang, Woong Mο; Arfuso, Frank; Um, Jae‐Young; Kumar, Alan Prem; Bian, Jin-Song; Sethi, Gautam; Ahn, Kwang Seok

doi:10.1016/j.canlet.2018.05.038

Cited by 160 publications

(143 citation statements)

References 70 publications

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“…STAT3 and NF‐κB are important transcription factors in signaling pathways, because tyrosine and serine phosphorylation causes their translocation to the nucleus, where they bind to DNA and regulate gene transcription, so their transcription activity or DNA binding ability is also crucial indicators to their expression. Some studies have shown that licorice extracts suppressed the DNA binding ability of STAT3 and NF‐κB when it exerts an antitumor or anti‐inflammatory effect, such as ISL and formononetin could reduce the constitutive phosphorylation and DNA‐binding activity of STAT3 in Caki cells and multiple myeloma (Kim et al, ; Kim et al, ). In addition, liquiritigenin and quercetin also could attenuate the NF‐κB NDA binding ability in Raw264.7 and HepG2 cells (Kim et al, ; Musonda & Chipman, ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying isoliquiritigenin‐induced apoptosis and cell cycle arrest via ROS‐mediated MAPK/STAT3/NF‐κB pathways in human hepatocellular carcinoma cells

Wang

Luo

Piao

et al. 2019

Drug Development Research

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Isoliquiritigenin (ISL), a natural flavonoid isolated from plant licorice, has various pharmacological properties, including anticancer, anti‐inflammatory, and antiviral effects. However, the underlying mechanisms and signaling pathways of ISL in human hepatocellular carcinoma (HCC) cells remain unknown. In this study, we evaluated the effects of ISL on the apoptosis of human HCC cells with a focus on reactive oxygen species (ROS) production. Our results showed that ISL exhibited cytotoxic effects on two human liver cancer cells in a dose‐dependent manner. ISL significantly induced mitochondrial‐related apoptosis and cell cycle arrest at the G2/M phase, which was accompanied by ROS accumulation in HepG2 cells. However, pretreatment with an ROS scavenger, N‐acetyl‐l‐cysteine (NAC), inhibited ISL‐induced apoptosis. In addition, ISL increased the phosphorylation levels of c‐Jun N‐terminal kinase (JNK), p38 kinase and inhibitor of NF‐κB (IκB), and decreased the phosphorylation levels of extracellular signal‐regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), nuclear factor‐kappa B (NF‐κB), these effects were blocked by NAC and mitogen‐activated protein kinase (MAPK) inhibitors. Taken together, the findings of this study indicate that ISL induced HepG2 cell apoptosis via ROS‐mediated MAPK, STAT3, and NF‐κB signaling pathways. Therefore, ISL may be a potential treatment for human HCC, as well as other cancer types.

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Section: Discussionmentioning

confidence: 99%

Mechanisms underlying isoliquiritigenin‐induced apoptosis and cell cycle arrest via ROS‐mediated MAPK/STAT3/NF‐κB pathways in human hepatocellular carcinoma cells

Wang

Luo

Piao

et al. 2019

Drug Development Research

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“…Formononetin , a potent phytoestrogen, is demonstrated with promising pharmacological effects, including anti-neoplastic action. 16 Our previous findings suggest that FN exerts effective activities for inhibiting OGS in vitro and in vivo. TP53 has many mechanisms of anti-cancer function and plays a role in apoptosis, genomic stability and inhibition of angiogenesis.…”

Section: Discussionmentioning

confidence: 95%

Anti‐cancer targets of formononetin and molecular mechanisms in osteosarcoma: Findings of bioinformatic and experimental assays

Zhao³

et al. 2019

J Cellular Molecular Medi

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In current study, a bioinformatic‐based network pharmacology was used to identify the osteosarcoma ( OGS )‐pathological targets and formononetin ( FN )‐treated targets before the main core predictive biotargets were screened. In addition, all core targets were selected through a number of bioinformatic databases, followed by identification of predominant biological processes and signalling pathways of FN anti‐ OGS . Further, top three core targets of FN anti‐ OGS were determined as oestrogen receptor 1 ( ESR 1), tumour protein p53 ( TP 53), receptor tyrosine‐protein kinase erbB‐2 ( ERBB 2) respectively. In clinical biochemical data, the plasma samples of OGS showed the increased trends of alkaline phosphatase, triglyceride, blood glucose, lactate dehydrogenase, high‐sensitive C‐reactive protein and some immune cell counts when referenced to medical criteria. In clinicopathological examination, histological OGS sections resulted in increased positive cell counts of neoplastic ESR 1, TP 53, ERBB 2. To further validate these corn proteins in experimental study in vivo, FN ‐treated tumour‐bearing nude mice showed intracellular reductions of ESR 1, TP 53, ERBB 2 positive expressions, accompanied with visibly reduced tumour weights. Collectively, our bioinformatic and experimental findings disclosed main core targets, biological processes and signalling pathways of FN anti‐ OGS . Interestingly, the top core targets were representatively validated following FN treatment in vivo. Therefore, we reasoned that these predictive targets might be the potential biomarkers for screening and treating osteosarcoma.

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“…EMSA was performed to analyze the interaction of STAT3-DNA as described previously [47,48]. Briefly, cells were subjected to ACHP treatment (10 µM for 4 h) and the nuclear extract was prepared.…”

Section: Electrophoretic Mobility Shift Assay (Emsa)mentioning

confidence: 99%

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

et al. 2019

Self Cite

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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented.In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

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Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model

Cited by 160 publications

References 70 publications

Mechanisms underlying isoliquiritigenin‐induced apoptosis and cell cycle arrest via ROS‐mediated MAPK/STAT3/NF‐κB pathways in human hepatocellular carcinoma cells

Mechanisms underlying isoliquiritigenin‐induced apoptosis and cell cycle arrest via ROS‐mediated MAPK/STAT3/NF‐κB pathways in human hepatocellular carcinoma cells

Anti‐cancer targets of formononetin and molecular mechanisms in osteosarcoma: Findings of bioinformatic and experimental assays

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

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