Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells

Lis, Christian; Rubner, Stefan; Roatsch, Martin; Berg, Angela; Gilcrest, Tyler; Fu, Darwin Y.; Nguyen, Elizabeth Dong; Schmidt, Annemarie; Krautscheid, Harald; Meiler, Jens; Berg, Thorsten

doi:10.1038/s41598-017-17600-x

Cited by 20 publications

(16 citation statements)

References 52 publications

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“…It thereby inhibits receptor autophosphorylation and blocks downstream signals 16 . Erlotinib is used in treatment of different types of cancer as lung cancer 17 and head and neck squamous cell carcinoma 18 . Many studies showed beneficial effects of erlotinib in different kidney injuries.…”

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confidence: 99%

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Awad

Saleh

Abu-Elsaad

et al. 2020

Sci Rep

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Renal fibrosis is a failed regenerative process that facilitates chronic kidney disease progression. The current study was designed to study the effect of erlotinib, a receptor tyrosine kinase inhibitor, on the progression of renal fibrosis. The study included four groups of mice: control group; adenine group: received adenine (0.2% w/w) daily with food for 4 weeks; erlotinib group: received 80 mg/ kg/day erlotinib orally (6 ml/kg/day, 1.3% w/v suspension in normal saline 0.9%) for 4 weeks; adenine + erlotinib group: received adenine and erlotinib concurrently. Kidney function and antioxidant biomarkers were measured. Renal expression of Bcl2 and p53 and histopathological changes (tubular injury and renal fibrosis) were scored. Renal tissue levels of transforming growth factor-β 1 , p-ERK1/2 and p-STAT3 were measured. Results obtained showed significant decrease (P < 0.001) in serum creatinine, urea and uric acid in erlotinib + adenine group. Level of malondialdehyde was decreased significantly (P < 0.001) while reduced glutathione and catalase levels were increased (P < 0.01) by erlotinib concurrent administration. Erlotinib markedly reduced fibrosis and tubular injury and decreased TGF-β1, p-ERK1/2 and p-STAT3 (P < 0.5). In addition, expression level of Bcl-2 was elevated (P < 0.001) while that of p53-was reduced compared to adenine alone. Erlotinib can attenuate renal fibrosis development and progression through anti-fibrotic, antioxidant and antiapoptotic pathways. Chronic kidney disease (CKD) is a global health burden and is considered as an independent risk factor for cardiovascular diseases. Its prevalence is correlated to many health problems as diabetes, hypertension and obesity 1, 2. Renal fibrosis is a failed regenerative process that facilitates the development of CKD. The progression of renal insufficiency in patients with CKD is mainly due to tubulointerstitial fibrosis, glomerular inflammation and tubular atrophy 3. Many cellular events are involved in tubulointerstitial fibrosis as infiltration of inflammatory cells, fibroblast activation, extracellular matrix (ECM) deposition and microvascular rarefaction 4. Various mediators are involved in the development of CKD and may represent possible targets for therapy such as transforming growth factor (TGF)-β, nuclear factor-erythroid 2 related factor, peroxisome proliferatoractivated γ receptor, IL-11 and advanced glycation endproducts 5, 6. Recently, studies reported involvement of miRNA in the progression of CKD progression 7. Tyrosine kinases have a pivotal role in cell signalling, and their activity deregulation can promote the development and progression of fibrotic diseases. As a result, pathologic activation of tyrosine kinases can drive fibrogenesis 8. Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, has been identified in renal tissue mainly in the epithelial cells of distal and collecting tubules, peritubular vessels and glomeruli with more abundant expression in diseased than in normal kidneys 9, 10. Activation of these r...

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confidence: 99%

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Awad

Saleh

Abu-Elsaad

et al. 2020

Sci Rep

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“…Previous study has shown that STAT3 dimerization is blocked and complex formation of STAT3 is impaired by Toosendanin, a triterpenoid saponin compound, which can inhibit osteosarcoma growth and metastasis ( Zhang et al, 2017 ). In addition, other study has reported that Erasin promotes apoptosis in Erlotinib-resistant lung cancer cells by direct inhibition of tyrosine phosphorylation of STAT3 ( Lis et al, 2017 ). Moreover, a recent study has demonstrated that S3I-201.1066, a novel small-molecule, binds with a high affinity to STAT3, disrupts STAT3 activation and function, and thereby increases anti-breast cancer activity in vitro and in vivo ( Zhang et al, 2010 ; Yeh and Frank, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3

Qiu

Shao

et al. 2018

Front. Pharmacol.

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Signal transducer and activator of transcription 3 (STAT3) is an attractive therapeutic target for cancer treatment. In this study, we identify lycorine is an effective inhibitor of STAT3, leading to repression of multiple oncogenic processes in colon carcinoma. Lycorine selectively inactivates phospho-STAT3 (Tyr-705), and subsequent molecular docking uncovers that lycorine directly binds to the SH2 domain of STAT3. Consequently, we find that lycorine exhibits anti-proliferative activity and induces cell apoptosis on human colorectal cancer (CRC) in vitro. Lycorine induces the activation of the caspase-dependent mitochondrial apoptotic pathway, as indicated by activation of caspase and increase of the ratio of Bax/Bcl-2 and mitochondrial depolarization. Overexpressing STAT3 greatly blocks these effects by lycorine in CRC cells. Finally, lycorine exhibits a potential therapeutic effect in xenograft colorectal tumors by targeting STAT3 without observed toxicity. Taken together, the present study indicates that lycorine acts as a promising inhibitor of STAT3, which blocks tumorigenesis in colon carcinoma.

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“…The fluorescence polarization assays were performed at approximately 37 • C, as described previously [77]. The final concentration of buffer components used for all fluorescence polarization (FP) assays was 10 mM HEPES (pH7.5), 1mM EDTA, 0.1% Nonidet P-40, 50mM NaCl, and 10% DMSO.…”

Section: Fluorescence Polarization Assaysmentioning

confidence: 99%

Trichothecin Inhibits Cancer-Related Features in Colorectal Cancer Development by Targeting STAT3

Zhang

et al. 2020

Molecules

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes to cancer progression through multiple processes of cancer development, which makes it an attractive target for cancer therapy. The IL-6/STAT3 pathway is associated with an advanced stage in colorectal cancer patients. In this study, we identified trichothecin (TCN) as a novel STAT3 inhibitor. TCN was found to bind to the SH2 domain of STAT3 and inhibit STAT3 activation and dimerization, thereby blocking STAT3 nuclear translocation and transcriptional activity. TCN did not affect phosphorylation levels of STAT1. TCN significantly inhibited cell growth, arrested cell cycle at the G0/G1 phase, and induced apoptosis in HCT 116 cells. In addition, the capacities of colony formation, migration, and invasion of HCT 116 cells were impaired upon exposure to TCN with or without IL-6 stimulation. In addition, TCN treatment abolished the tube formation of HUVEC cells in vitro. Taken together, these results highlight that TCN inhibits various cancer-related features in colorectal cancer development in vitro by targeting STAT3, indicating that TCN is a promising STAT3 inhibitor that deserves further exploration in the future.

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Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells

Cited by 20 publications

References 52 publications

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3

Trichothecin Inhibits Cancer-Related Features in Colorectal Cancer Development by Targeting STAT3

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