zearalenone and Neoplasms

ATPases Associated with Diverse Cellular Activity (AAA ATPase) are essential enzymes found in all organisms. They are involved in various processes such as DNA replication, protein degradation, membrane fusion, microtubule serving, peroxisome biogenesis, signal transduction, and the regulation of gene expression. Due to the importance of AAA ATPases, several researchers identified and developed small-molecule inhibitors against these enzymes. We discuss six AAA ATPases that are potential drug targets and have well-developed inhibitors. We compare available structures that suggest significant differences of the ATP binding pockets among the AAA ATPases with or without ligand. The distances from ADP to the His20 in the His-Ser-His motif and the Arg finger (Arg353 or Arg378) in both RUVBL1/2 complex structures bound with or without ADP have significant differences, suggesting dramatically different interactions of the binding site with ADP. Taken together, the inhibitors of six well-studied AAA ATPases and their structural information suggest further development of specific AAA ATPase inhibitors due to difference in their structures. Future chemical biology coupled with proteomic approaches could be employed to develop variant specific, complex specific, and pathway specific inhibitors or activators for AAA ATPase proteins.

Topics: ATPases Associated with Diverse Cellular Activities; Binding Sites; Carbazoles; Humans; Molecular Dynamics Simulation; Neoplasms; Pyrazoles; Pyrimidines; Quinazolines; Small Molecule Libraries; Zearalenone

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Topics: Animal Feed; Animals; Carcinogens; Edible Grain; Food Analysis; Foodborne Diseases; Humans; Mycotoxins; Neoplasms; Trichothecenes; Zearalenone

Topics: Animals; Carcinogens; China; Diet; Digestive System Neoplasms; Esophageal Neoplasms; Female; Fungi; Fusarium; Humans; Leukemia P388; Mice; Neoplasms; Resorcinols; Selenium; Sesquiterpenes; South Africa; Species Specificity; Trichothecenes; Zearalenone

Topics: Aflatoxins; Animals; Chemical and Drug Induced Liver Injury; Cytochalasins; Cytochrome P-450 Enzyme System; Cytoskeleton; Emodin; Energy Metabolism; Humans; Mutagens; Mycotoxins; Neoplasms; Protein Biosynthesis; Rats; Receptors, Estrogen; Zearalenone

Topics: Abnormalities, Drug-Induced; Aflatoxins; Animals; Climate; Female; Food Analysis; Food Contamination; Gastrointestinal Diseases; Genital Diseases, Female; Humans; Liver Diseases; Mycotoxins; Neoplasms; Neuromuscular Diseases; Plant Poisoning; Respiratory Tract Diseases; Skin Diseases; Sporidesmins; Trichothecenes; Zearalenone

The stereoselective total synthesis of zeaenol and 7-epi-zeaenol is achieved in a convergent manner using Julia-Kocienski olefination, protecting group-directed intermolecular diastereoselective Nozaki-Hiyama-Kishi (NHK) reaction, De Brabander's lactonization reaction and CBS reduction as the key steps. In this article, we have observed the most suitable protecting groups with respect to selectivity during the protecting group directed intermolecular asymmetric Nozaki-Hiyama-Kishi reaction. The zeaenol, 7-epi-zeaenol and its derivatives were analyzed for their biological activity and screened in four cancer cell lines.

Topics: Antineoplastic Agents; Ascomycota; Cell Line, Tumor; Humans; Neoplasms; Stereoisomerism; Zearalenone