Inhibition of Glycolysis Suppresses Cell Proliferation and Tumor Progression In Vivo: Perspectives for Chronotherapy

A high rate of glycolysis is considered a hallmark of tumor progression and is caused by overexpression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Therefore, we analyzed the possibility of inhibiting tumor and endothelial cell metabolism through the inhibition of PFKFB3 by a small molecule, (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15), as a promising therapy. The effects of PFK15 on cell proliferation and apoptosis were analyzed on human umbilical vein endothelial cells (HUVEC) and the human colorectal adenocarcinoma cell line DLD1 through cytotoxicity and proliferation assays, flow cytometry, and western blotting. The results showed that PFK15 inhibited the proliferation of both cell types and induced apoptosis with decreasing the Bcl-2/Bax ratio. On the basis of the results obtained from in vitro experiments, we performed a study on immunodeficient mice implanted with DLD1 cells. We found a reduced tumor mass after morning PFK15 treatment but not after evening treatment, suggesting circadian control of underlying processes. The reduction in tumor size was related to decreased expression of Ki-67, a marker of cell proliferation. We conclude that inhibition of glycolysis can represent a promising therapeutic strategy for cancer treatment and its efficiency is circadian dependent.     

Chemical,Pharmacological, and in vitro Metabolic Stability Studies on Enantiomerically Pure RC‐33 Compounds: Promising Neuroprotective Agents Acting as σ1 Receptor Agonists

Our recent research efforts identified racemic RC‐33 as a potent and metabolically stable σ₁ receptor agonist. Herein we describe the isolation of pure RC‐33 enantiomers by chiral chromatography, assignment of their absolute configuration, and in vitro biological studies in order to address the role of chirality in the biological activity of these compounds and their metabolic processing. The binding of enantiopure RC‐33 to the σ₁ receptor was also investigated in silico by molecular dynamics simulations. Both RC‐33 enantiomers showed similar affinities for the σ₁ receptor and appeared to be almost equally effective as σ₁ receptor agonists. However, the R‐configured enantiomer showed higher in vitro hepatic metabolic stability in the presence of NADPH than the S enantiomer. Overall, the results presented herein led us to select (R)‐RC‐33 as the optimal candidate for further in vivo studies in an animal model of amyotrophic lateral sclerosis.     

Self-Renewal and Cancers of the Gastric Epithelium: An Update and the Role of the Lectin TFF1 as an Antral Tumor Suppressor

In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5⁺ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells.