scholarly journals Ethacrynic Acid Enhances the Antitumor Effects of Afatinib in EGFR/T790M-Mutated NSCLC by Inhibiting WNT/Beta-Catenin Pathway Activation

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Xuehui Zhang ◽  
Chaoyuan Huang ◽  
Biyu Cui ◽  
Yebin Pang ◽  
Rong Liang ◽  
...  
Keyword(s):  
Ethacrynic Acid ◽  
Acquired Resistance ◽  
New Drugs ◽  
Inflammatory Factors ◽  
Beta Catenin ◽  
Antitumor Effects ◽  
Dual Inhibitor ◽  
Cytotoxic Effects ◽  
Pathway Activation ◽  
Egfr T790m

Background. Despite afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion or other rare EGFR-mutation patients, the acquired resistance or toxic effects associated with it limited its use clinically. The controlling of acquired resistance or optimization of the afatinib dosage in EGFR/T790M mutation-positive non-small-cell lung cancer (NSCLC) is still an important fundamental problem. Ethacrynic acid (EA) has been proved as a dual inhibitor of GST and WNT, and the α, β-unsaturated-keto structure of it is similar to that of irreversible tyrosine kinase inhibitors (TKIs). However, these beneficial effects of EA combined with afatinib have never been reported in NSCLC. Therefore, the antitumor effects of afatinib combined with EA in EGFR L858R/T790M-mutated NSCLC cells and related mechanisms were analyzed. Our in vitro and in vivo results showed that EA has strong synergistic antitumor effects with afatinib in EGFR L858R/T790M-mutated NSCLC cells, but has no cytotoxic effects in NSCLC cells when used it alone, i.e., the cytotoxic effects of afatinib (IC30) plus EA (IC30) were stronger than the effects of afatinib (IC50) alone. Our functional studies found that the antitumor mechanisms of afatinib when combined with EA mainly occurred by inhibiting WNT/β-catenin pathway activation and suppression of the secretion of anti-inflammatory factors. These results revealed that combination of afatinib with EA derivatives not only provided a new therapeutic approach for EGFR/T790M-mutated NSCLC patients but also offered a new idea for developing new drugs or optimizing the dose of afatinib in clinical use in future antitumor therapy.

scholarly journals Polyphenols Extracted from Shanxi-Aged Vinegar Inhibit Inflammation in LPS-Induced RAW264.7 Macrophages and ICR Mice via the Suppression of MAPK/NF-κB Pathway Activation

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2745
Author(s):  
Peng Du ◽  
Jia Song ◽  
Huirui Qiu ◽  
Haorui Liu ◽  
Li Zhang ◽  
...  
Keyword(s):  
Comprehensive Evaluation ◽  
Fermented Food ◽  
Gas Chromatography Mass Spectrometry ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Inflammatory Stress ◽  
Icr Mice ◽  
Raw264.7 Macrophages ◽  
Pathway Activation ◽  
Anti Inflammatory

Shanxi-aged vinegar, a traditional Chinese grain-fermented food that is rich in polyphenols, has been shown to have therapeutic effects on a variety of diseases. However, there has been no comprehensive evaluation of the anti-inflammatory activity of polyphenols extracted from Shanxi-aged vinegar (SAVEP) to date. The anti-inflammatory activities of SAVEP, both in RAW 264.7 macrophages and mice, were extensively investigated for the potential application of SAVEP as a novel anti-inflammatory agent. In order to confirm the notion that polyphenols could improve inflammatory symptoms, SAVEP was firstly detected by gas chromatography mass spectrometry (GC-MS). In total, 19 polyphenols were detected, including 12 phenolic acids. The study further investigated the protective effect of SAVEP on lipopolysaccharide-induced inflammation in RAW264.7 macrophages and ICR mice. The results showed that compared with those of the model group, SAVEP could remarkably recover the inflammation of macrophage RAW264.7 and ICR mice. SAVEP can normalise the expression of related proteins via the suppression of MAPK/NF-κB pathway activation, inhibiting the expression of iNOS and COX-2 proteins, and consequently the production of inflammatory factors, thus alleviating inflammatory stress. These results suggest that SAVEP may have a potential function against inflammation.

scholarly journals MicroRNA-182-5p relieves murine allergic rhinitis via TLR4/NF-κB pathway

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 1202-1212
Author(s):  
Aichun Zhang ◽  
Yangzi Jin
Keyword(s):  
Allergic Rhinitis ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Specific Ige ◽  
Inflammatory Factors ◽  
Pcr Analysis ◽  
Reverse Transcription Pcr ◽  
Pathway Activation ◽  
Nasal Lavage Fluid

AbstractAllergic rhinitis (AR) is one of the most common chronic diseases. This study examined whether microRNA (miR)-182-5p plays a role in AR by regulating toll-like receptor 4 (TLR4). First, data demonstrated that TLR4 was a target of miR-182-5p. Subsequently, AR mouse model was established to explore the role of miR-182-5p and TLR4 in AR in vivo. Initially, quantitative reverse transcription-PCR (qRT-PCR) analysis indicated that miR-182-5p was downregulated, while TLR4 expression was upregulated in AR mice. Then we found that miR-182-5p mimic reduced the frequency of sneezing and nose rubbing of the AR mice. In addition, miR-182-5p mimic significantly increased ovalbumin (OVA)-specific IgE and leukotriene C4 expression levels in nasal lavage fluid (NLF) and serum of AR mice. miR-182-5p mimic decreased the number of inflammatory cells in NLF of AR mice. It also reduced the levels of inflammatory factors in the serum of AR mice, such as interleukin (IL)-4, IL-5, IL-13, IL-17 and tumor necrosis factor (TNF)-α, while increasing the release of IFN-γ and IL-2. Finally, miR-182-5p mimic inhibited NF-κB signaling pathway activation in AR mice. However, all effects of miR-182-5p mimic on AR mice were reversed by TLR4-plasmid. In conclusion, miR-182-5p/TLR4 axis may represent a novel therapeutic target for AR.

scholarly journals Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 6
Author(s):  
Silvia La Monica ◽  
Claudia Fumarola ◽  
Daniele Cretella ◽  
Mara Bonelli ◽  
Roberta Minari ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Nsclc Cell ◽  
Dual Inhibitor ◽  
Nsclc Patients ◽  
Egfr Mutated

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

scholarly journals Natural Products Targeting the Mitochondria in Cancers

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 92
Author(s):  
Yue Yang ◽  
Ping-Ya He ◽  
Yi Zhang ◽  
Ning Li
Keyword(s):  
Natural Products ◽  
Anticancer Drugs ◽  
Web Of Science ◽  
Keyword Search ◽  
Biological Activities ◽  
Natural Compounds ◽  
New Drugs ◽  
Antitumor Effects ◽  
Regulate Cell Growth ◽  
Anticancer Drug Discovery

There are abundant sources of anticancer drugs in nature that have a broad prospect in anticancer drug discovery. Natural compounds, with biological activities extracted from plants and marine and microbial metabolites, have significant antitumor effects, but their mechanisms are various. In addition to providing energy to cells, mitochondria are involved in processes, such as cell differentiation, cell signaling, and cell apoptosis, and they have the ability to regulate cell growth and cell cycle. Summing up recent data on how natural products regulate mitochondria is valuable for the development of anticancer drugs. This review focuses on natural products that have shown antitumor effects via regulating mitochondria. The search was done in PubMed, Web of Science, and Google Scholar databases, over a 5-year period, between 2015 and 2020, with a keyword search that focused on natural products, natural compounds, phytomedicine, Chinese medicine, antitumor, and mitochondria. Many natural products have been studied to have antitumor effects on different cells and can be further processed into useful drugs to treat cancer. In the process of searching for valuable new drugs, natural products such as terpenoids, flavonoids, saponins, alkaloids, coumarins, and quinones cover the broad space.

scholarly journals The Phytochemical Analysis of Vinca L. Species Leaf Extracts Is Correlated with the Antioxidant, Antibacterial, and Antitumor Effects

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3040
Author(s):  
Alexandra Ciorîță ◽  
Cezara Zăgrean-Tuza ◽  
Augustin C. Moț ◽  
Rahela Carpa ◽  
Marcel Pârvu
Keyword(s):  
Bacterial Infections ◽  
Inhibitory Effect ◽  
Total Phenolic ◽  
Phytochemical Analysis ◽  
Leaf Extracts ◽  
Antitumor Effects ◽  
Cytotoxic Effects ◽  
E Coli ◽  
Lactate Dehydrogenase Release ◽  
Nitric Oxide Concentration

The phytochemical analysis of Vinca minor, V. herbacea, V. major, and V. major var. variegata leaf extracts showed species-dependent antioxidant, antibacterial, and cytotoxic effects correlated with the identified phytoconstituents. Vincamine was present in V. minor, V. major, and V. major var. variegata, while V. minor had the richest alkaloid content, followed by V. herbacea. V. major var. variegata was richest in flavonoids and the highest total phenolic content was found in V. herbacea which also had elevated levels of rutin. Consequently, V. herbacea had the highest antioxidant activity followed by V. major var. variegata. Whereas, the lowest one was of V. major. The V. minor extract showed the most efficient inhibitory effect against both Staphylococcus aureus and E. coli. On the other hand, V. herbacea had a good anti-bacterial potential only against S. aureus, which was most affected at morphological levels, as indicated by scanning electron microscopy. The Vinca extracts acted in a dose-depended manner against HaCaT keratinocytes and A375 melanoma cells and moreover, with effects on the ultrastructure, nitric oxide concentration, and lactate dehydrogenase release. Therefore, the Vinca species could be exploited further for the development of alternative treatments in bacterial infections or as anticancer adjuvants.

YAP confers resistance to vandetanib in medullary thyroid cancer

2020 ◽  
Vol 98 (3) ◽  
pp. 443-448
Author(s):  
Huan Wang ◽  
Jian Tang ◽  
Zhiwei Su
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Critical Role ◽  
Acquired Resistance ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Antitumor Effects ◽  
Medullary Thyroid ◽  
Tt Cells

Medullary thyroid cancer (MTC) is the third most common thyroid cancer. RET (Rearranged in Transformation) gene mutations are considered as one of the major drivers of MTC. Vandetanib suppresses RET activity, and has shown promise in clinical trials. Unfortunately, acquired resistance to vandetanib has been observed in MTC, although the mechanism was largely unknown. We investigated the critical role of YAP (Yes-Associated Protein) on vandetanib resistance in MTC. For this, TT cells (medullary thyroid cancer cells) were treated with vandetanib for 3 months to generate a vandetanib-resistant cell line (TT-R). We investigated the role of YAP on vandetanib-resistance in TT-R cells by performing cell proliferation and colony formation assays, and examined the antitumor effects of YAP inhibitor and vandetanib in a mouse model of xenografted MTC. The TT-R cells displayed 6-fold higher IC50 to vandetanib than the TT cells. Overexpression of YAP resulted in resistance to vandetanib, whereas knockdown of YAP re-sensitized the TT-R cells to vandetanib. The YAP inhibitor synergized with vandetanib on tumor inhibition. Our results suggest that YAP plays an important role in acquired resistance to vandetanib in MTC, providing basis for combating MTC with YAP inhibitor and vandetanib.

scholarly journals Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5574
Author(s):  
Filipe G. A. Estrada ◽  
Silvia Miccoli ◽  
Natália Aniceto ◽  
Alfonso T. Garcia-Sosa ◽  
Rita C. Guedes
Keyword(s):  
Multiple Myeloma ◽  
Drug Discovery ◽  
Chemical Space ◽  
Acquired Resistance ◽  
Developed Countries ◽  
Qsar Model ◽  
Neoplastic Disease ◽  
Dual Inhibitor ◽  
Dual Targeting ◽  
Proteasome 20S

Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.

Sign in / Sign up

Export Citation Format

Share Document