A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non-small cell lung cancers.

Tumor angiogenesis is closely associated with the metastasis and progression of non-small cell lung cancer (NSCLC), a highly vascularized solid tumor. However, novel therapeutics are lacking for the treatment of this cancer. Here, we developed a series of 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazol analogs (6a-6x) as tubulin colchicine-binding site inhibitors, aiming to find a novel promising drug candidate for NSCLC treatment. We first identified 2-(2-fluorophenyl)-3-(3,4,5-trimethoxybenzoyl)-5-(3-hydroxyazetidin-1-yl)-2H-1,2,3-triazole (6h) as a hit compound, which inhibited angiogenesis induced by NSCLC cells both in vivo and in vitro. In addition, our data showed that 6h could tightly bind to the colchicine-binding site of tubulin and inhibit tubulin polymerization. We also found that 6h could effectively induce G2/M cell cycle arrest of A549 and H460 cells, inhibit cell proliferation, and induce apoptosis. Furthermore, we showed 6h had the potential to inhibit the migration and invasion of NSCLC cells, two basic characteristics of tumor metastasis. Finally, we found 6h could effectively inhibit tumor progression in A549 xenograft mouse models with minimal toxicity. Taken together, these findings provide strong evidence for the development of 6h as a promising microtubule colchicine-binding site inhibitor for NSCLC treatment.

Isoniazide modified Ag nanoparticles triggered photothermal immunoassay for carcinoembryonic antigen detection.

As the most well-known analytical tool, the thermometer has been extended to the field of biological analysis based on the photothermal effect. Herein, isoniazide modified Ag nanoparticles were prepared as nanolabels to build an immunoassay. The nanoparticles were characterized by transmission electron microscope (TEM), dynamic laser scattering (DLS), X-ray powder diffraction (XRD), and Fourier transform infrared (FT-IR). When the target protein was present, the sandwich immunoassay was developed and the photothermal reaction was triggered by isoniazide modified Ag nanoparticles. As a reducing agent, isoniazide is used to transform phosphomolybdic acid hydrate into molybdenum blue solution. And molybdenum blue had good photothermal stability and high photothermal conversion efficiency. The temperature variation of molybdenum blue solution showed a positive correlation with the concentration of carcinoembryonic antigen (CEA). Thus, the target protein of CEA was quantitative detection by thermometer. The linear response range is 0.1 ng mL-1 to 40 ng mL-1, and the detection limit is 0.08 ng mL-1. Moreover, the proposed protocol had satisfactory selectivity, accuracy, and reproducibility.

Vitamin B12 alleviates myocardial ischemia/reperfusion injury via the SIRT3/AMPK signaling pathway.

AIM: To examine the protective effect of vitamin B12 against myocardial ischemia/reperfusion (I/R) injury and elucidate its underlying mechanism of action. METHODS: Mice were subjected to myocardial I/R injury by left anterior descending coronary artery (LAD) occlusion followed by 24 h reperfusion. Cardiac function and injury were evaluated by echocardiography, triphenyl tetrazolium chloride (TTC) and cardiac troponin T (cTnT) staining, and measuring lactate dehydrogenase (LDH) levels. In addition, various molecular and biochemical methods, as well as RNA sequencing were used to determine the effects and mechanism of action of vitamin B12 on I/R injury. RESULTS: We found that high doses of vitamin B12 inhibited myocardial I/R injury. Furthermore, our data indicated that vitamin B12 supplementation alleviated cardiac dysfunction and injury by mitigating oxidative stress and apoptosis through downregulation of Nox2, the Ac-SOD2/SOD2 and Bax/Bcl-2 ratios and cleaved caspase-3 expression, and upregulation of SIRT3 expression and AMPK activity. However, these effects were largely reversed following treatment with the SIRT3 inhibitor, 3-TYP. Our RNA-sequencing data further demonstrated that vitamin B12 supplementation reduced inflammation during I/R injury. CONCLUSION: High doses of vitamin B12 supplements improved myocardial I/R injury by suppressing the accumulation of reactive oxygen species and apoptosis of myocardial tissue through modulation of the SIRT3/AMPK signaling pathway, while reducing inflammation. Our findings suggested that vitamin B12 administered at high doses could be a potential therapy for myocardial I/R damage.

The anti-MDR efficacy of YAN against A549/Taxol cells is associated with its inhibition on glycolysis and is further enhanced by 2-deoxy-d-glucose.

Aerobic glycolysis is a hallmark of malignant tumor. Here, the hyperactive glycolysis in multidrug-resistant A549/Taxol cells was demonstrated to be essential for maintaining the vigorous cell viability and drug resistance. 5-(4-ethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-amine (YAN), a newly synthesized tubulin inhibitor, could not only inhibit the glycolysis in A549 and A549/Taxol cells through down-regulating the glycolysis-related proteins, but also disrupt the mitochondrial localization of hexokinase-2 (HK-2) which is related with the apoptosis resistance. The effects of YAN above were relevant to the down-regulation of PI3K-Akt-c-Myc/HIF-1α pathway. Moreover, YAN induced the reactive oxygen species generation in A549 and A549/Taxol cells, which only mediated the apoptosis in A549 cells. We also showed that 2-DG, the glycolysis inhibitor, synergistically enhanced YAN-triggered apoptosis in A549/Taxol cells via further suppressing glycolysis and reducing mitotic slippage. Collectively, we illustrate the inhibition effect of YAN on the glycolysis in A549 and A549/Taxol cells, and provide a fresh insight into the mechanism for the development of YAN as a candidate for multidrug resistant cancer treatment. The finding that 2-DG improved the anti-tumor efficacy of YAN against A549/Taxol cells, offers a reference for solving mitotic slippage-mediated drug resistance.