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Background: NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) is one of the ubiquitin-like proteins which is activated by the NEDD8 activating enzyme (NAE). The overexpressed NAE can cause a variety of diseases such as numerous cancer types and inflammatory diseases. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment., Objective: In this article, we decided to study the synthesis and screening of coumarin scaffold derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3., Methods: Twenty-four targeted compounds were synthesized, and their anti-proliferative activity against three cancer cell lines, cytotoxicity against three normal cell lines through CCK-8 and MTT assay were evaluated to screen out the candidate compound. Then the target was further confirmed by both enzyme and cell-based experiments, as well as cell apoptosis research., Results: Several new 4-position substituted coumarin derivatives (12a~x) were synthesized and most of them exhibit antiproliferative activity in three cancer cell lines. A series of experiments were performed to identify the best candidate compound 12v. This compound displayed the highest potency against BxPC-3 with an IC50 value of 0.28 μM. It can also inhibit NAE activity in enzyme and cellbased assay, and induce CRLs-mediated accumulation of the substrate and apoptosis in BxPC-3 cells. Meanwhile, it exhibited relatively low toxicity in three normal cells., Conclusion: Based on these results, we found that compound 12v inhibited NAE activity in enzyme and cell-based systems and induced apoptosis in BxPC-3 cells. Additionally, it also had a low toxicity. These results suggested that 12v may be promising lead compounds for the development of new anticancer drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in carcinomas. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment., Objective: In this article, we decided to study the synthesis and screening of 4-amino substituted 2H-chromen-2-one derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3., Methods: After synthesis of twenty targeted compounds, we evaluated their anti-proliferative activity against six cancer cell lines, cytotoxicity against three normal cell lines through MTT assay, and hemolysis to screen out the candidate compound, which was further conducted drug-like physical property measurement, target confirmation by enzyme-based experiment, cell apoptosis, and synergistic effect research., Results: Starting from intermediates 4 and 5, several new 4-amino substituted 2H-chromen-2-one derivatives (9-28) were synthesized and evaluated for their cell activities using six cancer cell lines. We performed tests of cytotoxicity, hemolysis, ATP-dependent NAE inhibition in the enzyme- based system, apoptosis, and synergistic effect in BxPC-3 cells against the best candidate compound 21., Conclusion: Based on these results, we found that compound 21 inhibited NAE activity in an ATP-dependent manner in the enzyme-based system, induced apoptosis in BxPC-3 cells, and synergized with bortezomib on BxPC-3 cell growth inhibition. Additionally, it had low toxicity with reasonable Log P-value and water solubility., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Squamous cell carcinomas are the most common head and neck malignancies. Significant progress has been made in standard therapeutic methods combining surgery, radiation, and chemotherapy. Nevertheless, the 5-year survival rate remains at 40–50%. Immune checkpoint inhibitors (ICIs) are a new strategy for treating head and neck squamous cell carcinomas (HNSCCs). Still, the overall response and effective rates are poor, as HNSCCs are 'cold' tumors with an immunosuppressive tumor microenvironment (TME), limiting ICI's beneficial effects. In this case, transforming the tumor suppression microenvironment before using ICIs could be helpful. Oncolytic viruses (OVs) can transform cold tumors into hot tumors, improving the situation. Talimogene laherparepvec (T-VEC), oncolytic immunotherapy authorized for advanced melanoma, also showed good safety and antitumor activity in treating head and neck cancer and pancreatic cancer. In combination with pembrolizumab, T-Vec may have more anticancer efficacy than either drug alone. Therefore, understanding the mechanisms underpinning OVs and their potential synergism with ICIs could benefit patients with HNSCC. [ABSTRACT FROM AUTHOR]

Encapsulation and release of water-insoluble drugs has been a challenge. In this paper, a pH/glutathione (GSH) dual-responsive self-assembly based on graphene oxide (GO) was designed and fabricated for the effective delivery of the anti-cancer drug, quercetin (QU). The pH-sensitive poly(2-(diisopropylamino ethylmethacrylate) (PDPA) was synthesized and grafted onto GOvia a disulfide bond (GO–PDPA). Then, the hydrophobic QU was loaded onto GO–PDPA followed by coating with chitosan (CHI) to obtain a biological medium-stable GO-based self-assembly (GO–PDPA–CHI). Dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM) and X-ray photoelectron spectroscopy (XPS) were used to investigate their size and zeta-potential, morphology, and chemical structures. The coating of chitosan on GO–PDPA not only increased the pH sensitivity of the carrier but also reduced its drug leakage from 60% to 40% at a pH of 7.4. Drug release experiments also showed that under the stimulus of pH and GSH, the drug cumulative release amount was over 75%. The dual-sensitive GO-based self-assembly exhibits great potential as a drug carrier for hydrophobic drugs in cancer therapy. [ABSTRACT FROM AUTHOR]

Due to the difference of the intracellular microenvironment between tumor and normal cells, many stimuli-responsive drug carriers have been developed for precise drug delivery and improved treatment effect. In this paper, a multi responsive drug delivery system based on mesoporous silica nanoparticle (MSN) was prepared. A pH/ROS-sensitive polymer was designed and used to attach to the MSN surface, which acted as a smart nano-valve to prevent premature leakage of drugs. The carrier has been proved to release drugs selectively in simulated tumor microenvironment with lower pH and higher ROS content. And, by co-loading a photosensitizer with antitumor drug, the carrier could produce exogenous ROS under the near-infrared light irradiation, resulting in much quicker removing of the polymer and more drug release. Furtherly, the antitumor effect was evaluated by CCK-8 assay using normal and tumor liver cells. In short, the results of drug release and cell experiments both showed that the carriers had excellent anti-tumor cells effects. [Display omitted] [ABSTRACT FROM AUTHOR]