Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants

Amani, Hamed; Ajami, Marjan; Maleki, Solmaz Nasseri; Pazoki‐Toroudi, Hamidreza; Daglia, Maria; Sokeng, Arold Jorel Tsetegho; Lorenzo, Arianna Di; Nabavi, Seyed Fazel; Devi, Kasi Pandima

doi:10.1016/j.biochi.2017.08.007

Cited by 41 publications

(16 citation statements)

References 224 publications

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“…Matsuno et al and Xu et al described further double-digit micromolar STAT3 inhibitors, STX-0119 and Cpd30-12 (in cellular assays; Figure 3h,i) [72,73]. Furthermore, a number of natural products (or analogs thereof) and antioxidants have been proposed and identified as potential inhibitors of STATs, most particularly STAT3, displaying even single-digit micromolar inhibitory activities [74][75][76][77][78].…”

Section: Stat3 Inhibitorsmentioning

confidence: 98%

Direct Targeting Options for STAT3 and STAT5 in Cancer

Orlova

Wagner

Araujo

et al. 2019

Cancers

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Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.

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Section: Stat3 Inhibitorsmentioning

confidence: 98%

Direct Targeting Options for STAT3 and STAT5 in Cancer

Orlova

Wagner

Araujo

et al. 2019

Cancers

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“…The jak2/stat3 pathway plays an important role in various diseases 54 . Focal cerebral ischemia is often accompanied by activation of macrophages/microglia, leading to acute inflammatory responses and neuronal damage through aberrant activation of the jak2/stat3 pathway 55 .…”

Section: Resultsmentioning

confidence: 99%

Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling

Amani

Habibey

Shokri

et al. 2019

Sci Rep

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222

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Ischemic cerebral stroke is a major cause of death and morbidity. Currently, no neuroprotective agents have been shown to impact the clinical outcomes in cerebral stroke cases. Here, we report therapeutic effects of Se nanoparticles on ischemic stroke in a murine model. Anti-transferrin receptor monoclonal antibody (OX26)-PEGylated Se nanoparticles (OX26-PEG-Se NPs) were designed and synthesized and their neuroprotective effects were measured using in vitro and in vivo approaches. We demonstrate that administration of the biodegradable nanoparticles leads to resolution of brain edema, protection of axons in hippocampus region, and myelination of hippocampal area after cerebral ischemic stroke. Our nanoparticle design ensures efficient targeting and minimal side effects. Hematological and biochemical analyses revealed no undesired NP-induced changes. To gain mechanistic insights into the therapeutic effects of these particles, we characterized the changes to the relevant inflammatory and metabolic signaling pathways. We assessed metabolic regulator mTOR and related signaling pathways such as hippo, Ubiquitin-proteasome system (ERK5), Tsc1/Tsc2 complex, FoxO1, wnt/β-catenine signaling pathway. Moreover, we examined the activity of jak2/stat3 signaling pathways and Adamts1, which are critically involved in inflammation. Together, our study provides a promising treatment strategy for cerebral stroke based on Se NP induced suppression of excessive inflammation and oxidative metabolism.

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“…STAT3, a tyrosine phosphorylation of signal channel coupling bifunctional protein, exist in cell cytoplasm, plays an important role in transmitting signals [31]. It has been found that a variety of extracellular signals can activate STAT3, then forming a two dimers and come into the nucleus, to recognize and bind to specific DNA promoter, in order to regulate the transcriptional of the target gene [32,33]. STAT3 signal transduction pathway is activated in a variety of primary tumors and tumor derived cell lines [34], which plays an important role in the regulation of tumor cell growth, proliferation and apoptosis process, this is may be related to the activation of a series of target gene followed STAT3 activation [35,36].…”

Section: Discussionmentioning

confidence: 99%

The mechanism and tumor inhibitory study of Lagopsis supine ethanol extract on colorectal cancer in nude mice

Wei

Wang

Xia

et al. 2019

BMC Complement Altern Med

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Background: This study was aimed to determination the tumor inhibitory effect and explore the potential mechanisms of Lagopsis supine ethanol extract (Ls) on colorectal cancer. Methods: The cell growth inhibition experiment of Ls in colorectal cancer cell lines was determined by MTT method in the time course of 24, 48 and 72 h in four gradient drug concentrations. The protein expression levels of pSTAT3, pJAK2, STAT3, JAK2, Bcl-2 and caspase 3 were measured by Western blot method. The mRNA levels of the downstream genes of STAT3 were detected through semi-quantitative RT PCR. Sixty Balb/c-nude mice were xenograft with HCT116 colorectal cancer cells through subcutaneously. The xenografts were divided into five groups: model group, positive group (capecitabine 300 mg/kg) and three dosages of Ls treated groups (75, 150 and 300 mg/kg). Tumor size and tumor weight were calculated for evaluation the anti-tumor effects. H & E staining and immunohistochemical analysis were used to determine the histopathological changes and the levels of pSTAT3 and pJAK2 in the tumor tissues. Results: Ls exhibited a significant anti-proliferation effect in HCT116 and SW480 cells in vitro. The protein levels of pSTAT3, pJAK2 and Bcl-2, and the mRNA levels of Bcl-2 and Bak notably reduced with a dose-dependent manner. While the protein levels of caspase 3, and mRNA levels of Bax and caspase-3 remarkably increased in the gradient dosage of Ls in HCT116 cells. HCT116 in vivo xenografts experiment showed that the growth of the tumors significantly inhibited by Ls administration, which with no any significant body weight changes in each experiment group. The histopathology analysis displayed that Ls significantly reduced the inflammatory cells in tumor tissue. Furthermore, Ls also significantly down-regulate the protein levels of pSTAT3 and pJAK2 in the tumor tissues, compared with the model group. Conclusions: This work shows that Ls inhibited the cell proliferation of colorectal cancer in vitro and significantly reduced the tumor growth in HCT116 xenografts in vivo, which is probably related with the JAK/STAT signal pathway.

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Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants

Cited by 41 publications

References 224 publications

Direct Targeting Options for STAT3 and STAT5 in Cancer

Direct Targeting Options for STAT3 and STAT5 in Cancer

Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling

The mechanism and tumor inhibitory study of Lagopsis supine ethanol extract on colorectal cancer in nude mice

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