Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer

CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms. The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay. Tubulin cross-linking was used to identify the binding site of S516 on tubulin, and Western blotting was performed to identify the intracellular pathways leading to cell death. Subcutaneous lung cancer xenograft models were used to assess the in vivo effect of CKD-516 on tumor growth. S516 targeted the colchicine binding site on β-tubulin. In lung cancer cells, S516 increased endoplasmic reticulum (ER) stress and induced reactive oxygen species (ROS) generation by mitochondria and the ER. In addition, CKD-516 monotherapy strongly inhibited the growth of lung cancer xenograft tumors and exerted a synergistic effect with carboplatin. The findings suggest that CKD-516 exerts an anticancer effect in company with inducing ER stress and ROS production via microtubule disruption in lung cancer cells. CKD-516 may thus have therapeutic potential for lung cancer.     

Phenethyl Isothiocyanate Protects against High Fat/Cholesterol Diet-Induced Obesity and Atherosclerosis in C57BL/6 Mice

This study concerns obesity-related atherosclerosis, hyperlipidemia, and chronic inflammation. We studied the anti-obesity and anti-atherosclerosis effects of phenethyl isothiocyanate (PEITC) and explored their underlying mechanisms. We established an animal model of high fat/cholesterol-induced obesity in C57BL/6 mice fed for 13 weeks. We divided the mice into five groups: control (CON), high fat/cholesterol (HFCD), HFCD with 3 mg/kg/day gallic acid (HFCD + G), and HFCD with PEITC (30 and 75 mg/kg/day; HFCD + P30 and P75). The body weight, total cholesterol, and triglyceride were significantly lower in the HFCD + P75 group than in the HFCD group. Hepatic lipid accumulation and atherosclerotic plaque formation in the aorta were significantly lower in both HFCD + PEITC groups than in the HFCD group, as revealed by hematoxylin and eosin (H&E) staining. To elucidate the mechanism, we identified the expression of genes related to inflammation, reverse cholesterol transport, and lipid accumulation pathway in the liver. The expression levels of peroxisome proliferator activated receptor gamma (PPARγ), liver-X-receptor α (LXR-α), and ATP binding cassette subfamily A member 1 (ABCA1) were increased, while those of scavenger receptor A (SR-A1), cluster of differentiation 36 (CD36), and nuclear factor-kappa B (NF-κB) were decreased in the HFCD + P75 group compared with those in the HFCD group. Moreover, PEITC modulated H3K9 and H3K27 acetylation, H3K4 dimethylation, and H3K27 di-/trimethylation in the HFCD + P75 group. We, therefore, suggest that supplementation with PEITC may be a potential candidate for the treatment and prevention of atherosclerosis and obesity.     

Children in the Blind Spot of Social Medical Concerns: Supporting Children with Mentally Ill Parents in Korea

Community Mental Health Journal - Children whose parents have mental disorders are more likely to be vulnerable and exposed to an environment where they may not be cared for by parents or guardians...