clozapine and Neoplasms

The dopamine D

Topics: Animals; Drug Discovery; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Parkinson Disease; Receptors, Dopamine D4; Small Molecule Libraries; Substance-Related Disorders

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

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitous cation channel possessing kinase activity. TRPM7 mediates a variety of physiological responses by conducting flow of cations such as Ca

Topics: Apoptosis; Autophagosomes; Autophagy; Cell Proliferation; Clozapine; Humans; Lysosomes; Naltrexone; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Protein Serine-Threonine Kinases; R-SNARE Proteins; Signal Transduction; TRPM Cation Channels; Zinc

Schizophrenia (SZ) is associated with increased all-cause mortality, smoking, and age-associated proteins, yet multiple previous studies found no association between SZ and biological age using Horvath's epigenetic clock, a well-established aging biomarker based on DNA methylation. However, numerous epigenetic clocks that may capture distinct aspects of aging have been developed. This study tested the hypothesis that altered aging in SZ manifests in these other clocks.. We performed a comprehensive analysis of 14 epigenetic clocks categorized according to what they were trained to predict: chronological age, mortality, mitotic divisions, or telomere length. To understand the etiology of biological age differences, we also examined DNA methylation predictors of smoking, alcohol, body mass index, serum proteins, and cell proportions. We independently analyzed 3 publicly available multiethnic DNA methylation data sets from whole blood, a total of 567 SZ cases and 594 nonpsychiatric controls.. All data sets showed accelerations in SZ for the 3 mortality clocks up to 5 years, driven by smoking and elevated levels of 6 age-associated proteins. The 2 mitotic clocks were decelerated in SZ related to antitumor natural killer and CD8T cells, which may help explain conflicting reports about low cancer rates in epidemiological studies of SZ. One cohort with available medication data showed that clozapine is associated with male-specific decelerations up to 7 years in multiple chronological age clocks.. Our study demonstrates the utility of studying the various epigenetic clocks in tandem and highlights potential mechanisms by which mental illness influences long-term outcomes, including cancer and early mortality.

Topics: Aging; Biomarkers; Clozapine; DNA Methylation; Epigenesis, Genetic; Humans; Male; Neoplasms; Schizophrenia

Topics: Aging; Biomarkers; Clozapine; Epigenesis, Genetic; Humans; Neoplasms; Schizophrenia

Topics: Aging; Biomarkers; Clozapine; Epigenesis, Genetic; Humans; Neoplasms; Neuroimaging; Psychotic Disorders; Schizophrenia; Transcriptome

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRP

Topics: Adenomatous Polyposis Coli Protein; Animals; Anorexia; Behavior, Animal; Body Weight; Cachexia; Calcitonin Gene-Related Peptide; Carcinoma, Lewis Lung; Clozapine; Energy Metabolism; Female; Illness Behavior; Male; Metalloendopeptidases; Mice; Mice, Transgenic; Neoplasms; Parabrachial Nucleus; Tetanus Toxin; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Agents; Antipsychotic Agents; Bleomycin; Breast Neoplasms; Carcinoma; Cisplatin; Clozapine; Etoposide; Female; Humans; Intestinal Neoplasms; Male; Middle Aged; Neoplasms; Neutropenia; Schizophrenia; Seminoma; Testicular Neoplasms

Activating mutations in GNAQ and GNA11, encoding members of the Gα(q) family of G protein α subunits, are the driver oncogenes in uveal melanoma, and mutations in Gq-linked G protein-coupled receptors have been identified recently in numerous human malignancies. How Gα(q) and its coupled receptors transduce mitogenic signals is still unclear because of the complexity of signaling events perturbed upon Gq activation. Using a synthetic-biology approach and a genome-wide RNAi screen, we found that a highly conserved guanine nucleotide exchange factor, Trio, is essential for activating Rho- and Rac-regulated signaling pathways acting on JNK and p38, and thereby transducing proliferative signals from Gα(q) to the nucleus independently of phospholipase C-β. Indeed, whereas many biological responses elicited by Gq depend on the transient activation of second-messenger systems, Gq utilizes a hard-wired protein-protein-interaction-based signaling circuitry to achieve the sustained stimulation of proliferative pathways, thereby controlling normal and aberrant cell growth.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Clozapine; Drosophila; Drosophila Proteins; Enzyme Activation; Female; Gene Knockdown Techniques; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Guanine Nucleotide Exchange Factors; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; Mitogens; Mitosis; Neoplasm Transplantation; Neoplasms; NIH 3T3 Cells; Protein Serine-Threonine Kinases; Receptors, G-Protein-Coupled; rho GTP-Binding Proteins; RNA Interference; Signal Transduction; Transcription Factor AP-1

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

Topics: Animals; Benzamides; Cardiovascular Diseases; Clinical Trials as Topic; Clozapine; Depression; Drug Approval; Drug Design; Drug Evaluation, Preclinical; Drug Industry; Gefitinib; Humans; Imatinib Mesylate; Neoplasms; Piperazines; Pyrimidines; Quinazolines; Sensitivity and Specificity; Substrate Specificity; Therapeutics; United States; United States Food and Drug Administration