Matrine suppresses cell growth of human chronic myeloid leukemia cells via its inhibition of the interleukin-6/Janus activated kinase/signal transducer and activator of transcription 3 signaling cohort

et al. 2017

JAHA

BackgroundThe matrine‐type alkaloids are bioactive components extracted from Sophora flavescens, which is used in treatment of diabetes mellitus in traditional Chinese medicine. Advanced glycation end products mediate diabetic vascular complications. This study was aimed to investigate the protective effects and molecular mechanisms of matrine‐type alkaloids on advanced glycation end products–induced reactive oxygen species–mediated endothelial apoptosis.Methods and ResultsRats aorta and cultured rat aortic endothelial cells were exposed to advanced glycation end products. Matrine‐type alkaloids, p38 mitogen‐activated protein kinase (MAPK) inhibitor, and small interference RNAs against p38 MAPK kinases MAPK kinase kinase (MKK)3 and MKK6 were administrated. Intracellular reactive oxygen species production, cell apoptosis, phosphorylation of MKKs/p38 MAPK, and expression levels of heme oxygenase/NADPH quinone oxidoreductase were assessed. The nuclear factor erythroid 2‐related factor 2 nuclear translocation and the binding activity of nuclear factor erythroid 2‐related factor 2 with antioxidant response element were also evaluated. Matrine‐type alkaloids suppressed intracellular reactive oxygen species production and inhibited endothelial cell apoptosis in vivo and in vitro by recovering phosphorylation of MKK3/6 and p38 MAPK, nuclear factor erythroid 2‐related factor 2 nuclear translocation, and antioxidant response element binding activity, as well as the expression levels of heme oxygenase/NADPH quinone oxidoreductase. p38 MAPK inhibitor treatment impaired the effects of matrine‐type alkaloids in vivo and in vitro. MKK3/6 silencing impaired the effects of matrine‐type alkaloids in vitro.ConclusionsMatrine‐type alkaloids exert endothelial protective effects against advanced glycation end products induced reactive oxygen species–mediated apoptosis by targeting MKK3/6 and enhancing their phosphorylation.

Section: Introductionmentioning

confidence: 81%

mentioning

confidence: 99%

Matrine‐Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species‐Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling

Liu

et al. 2017

JAHA

“…Furthermore, JAK/STAT signaling pathway has been implicated in transmission of information carried by cytokines. It is reported that JAK/STAT3 pathway can be activated by IL6, thus contributes to the CML development (17). Kumar et al (25), also demonstrated that IL-6 can induce JAK/STAT and MAPK pathways, thus have a key role in deciphering the CML progression stages.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, luciferase reporter assay was performed to investigate whether interleukin-6 (IL6) was a target of miR-574-3p. Besides, it is reported that IL6 can regulate the activation of JAK/STAT3 pathway in CML development (17), thus the regulatory relationship between miR-574-3p and IL6/Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) pathway was explored. All efforts of our study were to elucidate the potential roles and regulatory mechanism of miR-574-3p in CML development.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of miR‑574‑3p suppresses proliferation and induces apoptosis of chronic myeloid leukemia cells via targeting IL6/JAK/STAT3 pathway

Yang

et al. 2018

Exp Ther Med

The present study aimed to elucidate the potential roles and regulatory mechanism of microRNA (miR)-574-3p in the development of chronic myeloid leukemia (CML). The expression of miR-574-3p in peripheral blood obtained from patients with CML was examined. Subsequently, miR-574-3p was overexpressed and suppressed in CML K562 cells to further investigate the effects of miR-574-3p on cell proliferation, and apoptosis. Furthermore, a luciferase reporter assay was performed to investigate whether interleukin-6 (IL-6) was a target of miR-574-3p. In addition, the regulatory association between miR-574-3p and the IL-6/Janus kinase (JNK)/signal transducer and activator of transcription-3 (STAT3) signaling pathway was explored. The expression of miR-574-3p in the peripheral blood obtained from patients with CML was significantly lower compared with that in healthy controls. Overexpression of miR-574-3p significantly inhibited the proliferation and induced the apoptosis of K562 cells, whereas suppression of miR-574-3p exhibited opposite effects. In addition, IL-6 was identified to be a direct target of miR-574-3p. Overexpression of IL-6 significantly promoted the proliferation and inhibited the apoptosis of K562 cells. Furthermore, overexpression of miR-574-3p inhibited the activation of the JAK/STAT3 signaling pathway, which was rescued by overexpression of IL-6. The results of the current study indicate that miR-574-3p overexpression may serve an important role in inhibiting proliferation and inducing apoptosis of K562 cells via suppression of IL-6/JAK/STAT3 signaling pathway activation. miR-574-3p may serve as a potential therapeutic target for CML.

“…It plays an important role in the regulation of IL-6 expression and activation of the JAK1/STAT3 signaling pathway (17–19,24). A number of previous studies have reported the effects of matrine on NSCLC cells with the T790M mutation, including H1975 cells, in the presence or absence of a TKI.…”

Section: Discussionmentioning

confidence: 99%

Matrine increases the inhibitory effects of afatinib on H1975 cells via the IL-6/JAK1/STAT3 signaling pathway

Chen

Molecular Medicine Reports

2017

Resistance to epidermal growth factor receptor (EGFR) inhibitors is of primary concern in the treatment of non-small-cell lung cancer (NSCLC) with EGFR mutations. To investigate the effects of matrine on H1975 cells and to examine a novel, potential treatment option for NSCLC, the present study measured cell viability, apoptotic rate, interleukin 6 (IL-6) expression and activation of the janus kinase (JAK) 1/signal transducer and activator of transcription (STAT)3 signaling pathway in cells treated with or without matrine, in the presence or absence of afatinib. The results demonstrated that matrine treatment inhibited cell growth, decreased B-cell lymphoma 2 (Bcl-2) expression and induced apoptosis. Matrine treatment additionally decreased the mRNA and protein levels of IL-6 and inhibited activation of the JAK1/STAT3 signaling pathway in H1975 cells in a dose-dependent manner. H1975 cells treated with IL-6 small interfering RNA exhibited a decrease in Bcl-2 expression levels and cell viability. Treatment with a combination of matrine and afatinib demonstrated increased inhibitory effects on the growth rate of H1975 cells. The findings of the present study suggested that matrine treatment decreases IL-6 expression, inhibits activation of the JAK1/STAT3 signaling pathway, reduces the expression levels of Bcl-2 and inhibits cell growth. Furthermore, matrine treatment was demonstrated to increase the inhibitory effects of afatinib on H1975 cells with the T790M EGFR mutation.