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Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1β inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model. [ABSTRACT FROM AUTHOR]

The effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. The solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. The anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. These results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) plays crucial roles in several cellular processes such as cell proliferation and survival, and has been found to be aberrantly activated in many cancers. Much research has explored the leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis. We focus here on recent evidence suggesting that feedback activation of STAT3 plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. We highlight the potential of co-targeting STAT3 and its primary target to overcome drug resistance, and provide perspective on repurposing clinically approved drugs as STAT3 pathway inhibitors, in combination with the FDA-approved receptor tyrosine kinase (RTK) inhibitors, to improve clinical outcome of cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is one of the most common types of malignant tumor. It has one of the highest morbidity and mortality rates worldwide, and approximately 85% of cases are non-small cell lung cancer (NSCLC). Clinically, several EGFR inhibitors have been used to treat NSCLC, but resistance can develop. Studies have shown that cross talk between signal transducer and activator of transcription 3 (STAT3) and epidermal growth factor receptor (EGFR) can mediate drug resistance. Acetylshikonin has obvious antitumor effects, but the mechanism of action is still unclear.Purpose: To analyze the antitumor activity of acetylshikonin in lung cancer and clarify its molecular mechanism.Methods: Methyl thiazolyl tetrazolium (MTT), colony formation and 5-ethynyl-2'-deoxyuridine (EDU) assays were performed to examine the effects of acetylshikonin in inhibiting the proliferation of NSCLC cells (PC-9, H1975 and A549). Scratch wound and transwell assays were used to evaluate the migration and invasion of NSCLC cells. Flow cytometry was employed to determine whether acetylshikonin could induce apoptosis. Proteome sequencing was used to identify the targets of acetylshikonin. Immunofluorescence staining and western blotting were utilized to verify the inhibition of STAT3 and EGFR phosphorylation. A xenotransplantation model was established to evaluate the efficacy of acetylshikonin in nude mice.Results: Our data demonstrated that acetylshikonin significantly decreased the survival rate of human NSCLC cells, increased the apoptotic rate and inhibited cell migration dose-dependently. Immunofluorescence staining and western blotting analyses revealed that acetylshikonin inhibited EGFR and STAT3 pathways. Acetylshikonin also inhibited tumor growth in a xenograft model better than inhibitors of EGFR and STAT3.Conclusion: Acetylshikonin has anti-cancer effects on NSCLC cells by inhibiting EGFR and STAT3, indicating that acetylshikonin may be a new antitumor drug to treat NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin is a multifunctional natural product with regulatory effects on inflammation. However, a major limitation for the application of curcumin is its poor bioavailability. We previously demonstrated that the mono-carbonyl analogues of curcumin possessed improved pharmacokinetic profiles. In this study, 33 novel mono-carbonyl analogues of curcumin were synthesized and their inhibition against TNF-α and IL-6 release was evaluated in LPS-stimulated RAW 264.7 macrophages. Based on the screening data, quantitative structure–activity relationship was conducted, indicating that electron-withdrawing groups in benzene ring are favourable to anti-inflammatory activities of B-class compounds. Furthermore, compounds AN1 and B82 demonstrated anti-inflammatory abilities in a dose-dependent manner. These raise the possibility that these compounds might serve as potential agents for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin has been reported to possess multifunctional bioactivities, especially the ability to inhibit proinflammatory induction. We previously demonstrated that the mono-carbonyl analogues of curcumin possessed improved pharmacokinetic profiles both in vitro and in vivo. In this study, we synthesized and examined a series of 5-carbon linker-containing mono-carbonyl analogues of curcumin with potent inhibitory activities against TNF-α and IL-6 release in LPS-stimulated RAW 264.7 macrophages. Discussion and conclusions are given regarding structure-activity relationships (SAR). The two most potent analogues among the tested compounds, B75 and C12, exhibited anti-inflammatory abilities in a dose-dependent manner in macrophages. This raises the possibility that mono-carbonyl analogues of curcumin might serve as potential agents for the treatment of various inflammatory diseases. [Copyright &y& Elsevier]

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide. Corylin is an isoflavone extracted from Cullen corylifolium (L.) Medik., which is widely used anti-inflammatory and anticancer in Asian countries. Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and development of CRC.Purpose: To analyze the antitumor activity of corylin in CRC and to elucidate its molecular mechanisms of action.Methods: The human CRC cell lines HCT116, RKO, and SW480 and immunodeficient mice were used as models to study the antitumor effect of corylin. The potent anti-proliferative, anti-migration and proapoptotic effects of corylin were observed by cell viability, colony formation assays, wound-healing migration assay, and cell apoptosis assay. Immunostaining analysis and western blot analysis revealed inhibition of the STAT3 signaling axis.Results: We found that corylin could significantly reduce the viability and stimulate apoptosis in human CRC cells in a dose-dependent manner. Corylin decreased the expression levels of P-STAT3 and STAT3 target proteins, such as myeloid cell leukemia-1(MCL-1), Survivin, VEGF and B-cell lymphoma 2 (BCL-2). It also upregulated the expression levels of the proapoptotic proteins BCL-2-associated X protein (BAX) and Cl-caspase 3. Moreover, corylin reduced the nuclear localization of STAT3. Furthermore, corylin inhibited the growth of the tumor in CRC mouse models.Conclusions: Our findings provide convincing results that could support the role of corylin in the treatment of CRC through inhibiting the STAT3 pathway. It is conceivable that corylin should be further explored as a unique STAT3 inhibitor in antitumor therapy. [ABSTRACT FROM AUTHOR]

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling system regulates a variety of biological processes, including embryogenesis, angiogenesis, wound repair, tissue homeostasis, and cancer. It exerts these regulatory functions by controlling proliferation, differentiation, migration, survival, and metabolism of target cells. The morphological structure of the lung is a complex tree-like network for effective oxygen exchange, and the airway terminates in the middle and distal ends of many alveoli. FGF/FGFR signaling plays an important role in the pathophysiology of lung development and pathogenesis of various human respiratory diseases. Here, we mainly review recent advances in FGF/FGFR signaling during human lung development and respiratory diseases, including lung cancer, acute lung injury (ALI), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. [Display omitted] • The role of FGF/FGFR signaling in human lung development and respiratory disease remains poorly understood. • Many studies have shown the importance of FGF/FGFR signaling in the development of lung and in various respiratory diseases. • Understanding the role of FGF/FGFR signaling will help tailor its effects and targets to action sites and patients. [ABSTRACT FROM AUTHOR]

• Novel activators of STAT3 have diverse functions in regulating cancer cellular processes and have been validated as potential drug targets. • STAT3 activation is a resistance mechanism. • STAT3 inhibitors that show promise as new therapeutic leads can combined with chemotherapies to improve patient outcomes. Excessive activation of signal transducer and activator of transcription 3 (STAT3) signaling is observed in a subset of many cancers, making activated STAT3 a highly promising potential therapeutic target supported by multiple preclinical and clinical studies. However, early-phase clinical trials have produced mixed results with STAT3-targeted cancer therapies, revealing substantial complexity to targeting aberrant STAT3 signaling. This review discusses the diverse mechanisms of oncogenic activation of STAT3, and the small molecule inhibitors of STAT3 in cancer treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of cancer related deaths worldwide with the highest mortality rate. Non-small cell lung cancer (NSCLC) accounts for about 85 % of lung cancers. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme and is the most differentially expressed metabolic enzyme in various tumors including lung cancer. However, little is known about how MTHFD2 functions in NSCLC. Integrin-linked kinase (ILK) signaling plays key a role in tumor progression including metastasis, proliferation and migration. Here, we show that MTHFD2 inhibition results in suppression of cell growth, migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC. Microarray analysis suggests that MTHFD2 is positively associated with ILK signaling based on western blotting results. In addition, the phosphorylation of AMPKα plays an essential role in MTHFD2 regulation of ILK signaling. Further, the small-molecule compound C18 inhibits MTHFD2 with great efficiency. C18 blocks MTHFD2/ILK signaling pathway and restrains cell growth, migration, invasion, and EMT of NSCLC and induces apoptosis. In brief, our study found that the positive impact of MTHFD2 is mediated via ILK signaling pathway in NSCLC. Thus, blocking MTHFD2 represents a promising therapeutic strategy against NSCLC clinically. [Display omitted] • MTHFD2 promote the survival, migration and invasion in NSCLC cells. • MTHFD2 promote development of NSCLC by activating ILK signaling pathway. • AMPKα plays great role in the regulation of ILK signaling by MTHFD2. • Screen of novel small molecular compound C18 which suppressed MTHFD2 expression. • C18 restrains NSCLC development via MTHFD2/ILK signaling. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin has a surprisingly wide range of chemo-preventive and chemo-therapeutic activities and is under investigation for the treatment of various human cancers. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property. Although a number of synthetic modifications of curcumin have been studied intensively in order to develop a molecule with enhanced bioactivities, few synthetic studies were done for the improvement of pharmacokinetic profiles. In the present study, a series of mono-carbonyl analogues of curcumin were designed and synthesized by deleting the reactive β-diketone moiety, which was considered to be responsible for the pharmacokinetic limitation of curcumin. The results of the in vitro stability studies and in vivo pharmacokinetic studies indicated that the stability of these mono-carbonyl analogues was greatly enhanced in vitro and their pharmacokinetic profiles were also significantly improved in vivo. Furthermore, the cytotoxic activities of mono-carbonyl analogues were evaluated in seven different tumor cell lines by MTT assay and the structure–activity relation (SAR) was discussed and concluded. The results suggest that the five-carbon linker-containing analogues of curcumin may be favorable for the curcumin-based drug development both pharmacokinetically and pharmacologically. [Copyright &y& Elsevier]

Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner. A series of novel indazole derivatives were synthesized and evaluated for anti-cancer activities. The SAR analysis suggested that chloroacetamide warhead and 3,5-dimethoxyphenyl were favorable for FGFR4 selectivity. F-30 inhibited FGF19-induced FGFR4 phosphorylation and the phosphorylation of downstream kinases MAPK in a concentration-dependent manner in HUH7 cell lines. Furthermore, we have confirmed that F-30 inhibited migration, proliferation, and apoptosis of HCC cell lines. Further study confirmed that apoptosis was induced by DNA damage. Image 1 • Novel FGFR4 inhibitors as potent anti-cancer agents were conceived using CADD and structure-based design strategies. • Thirty-five novel indazole derivatives as potent fibroblast growth factor receptors (FGFR) inhibitors were synthesized. • F-30 exhibited potent activities in both enzymatic and cellular assays. • In vitro study indicated that compound F-30 is a potent and selective FGFR4 inhibitor. • F-30 covalently bound to FGFR4 protein. [ABSTRACT FROM AUTHOR]