ABSTRACT
Erythroleukemia is a malignant disease in the blood system. Quinones consists of a class of antitumor agents. Calothrixin B is a carbazole-1,4-quinone alkaloid isolated from Calothrix cyanobacteria with a unique indolo[3,2-j] phenanthridine framework. This study aimed to investigate the anti-leukemic effect of the new Calothrixin B derivative, L20, and to dig up the underlying mechanisms. Cytotoxicity analysis of L20 has revealed that it shows significant IC50 concentrations in HEL cells at low doses (1.10 ± 0.05 µM) than in K562, and KG-1a (5.46 ± 3.09, and 1.82 ± 1.08 µM respectively). The study even revealed that the L20 could induce a dose and time-dependent cellular death in HEL cells. The L20 increased expression of phospho-γ-H2A.X and phospho-p38 in HEL cells, causing DNA damage and nuclear alterations due to the G2/M phase cell cycle arrest. The HEL cells even lost the mitochondrial membrane potential (MMP) and resulted in the release of reactive oxygen species (ROS). Additionally, L20 inhibited the proliferation of HEL cells by inducing apoptosis through the mitochondrial pathway, depending on the caspase family. The study even established this may be due to the upregulation of the p-P38MAPK and downregulation of p-ERK. Pretreatment with P38/ERK inhibitors, SB203580, and U0126, decreased L20-induced apoptosis. These findings indicated that L20 induced mitochondrial mediated-apoptosis and G2/M arrest through DNA damage and modulation of p38 MAPK pathways. Thus, the study suggests L20, a chemical analog of Calothrixin B, as a novel chemotherapeutic agent against erythroleukemia.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Histones/metabolism , Leukemia/drug therapy , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Butadienes/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Genes, myb/drug effects , Humans , Imidazoles/pharmacology , Indole Alkaloids/chemistry , Leukemia/metabolism , Membrane Potential, Mitochondrial/drug effects , Molecular Docking Simulation , Nitriles/pharmacology , Pyridines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
The tetracyclic and pentacyclic skeletons of pyrido and quinolinocarbazole alkaloids have been synthesized via a unified strategy. The prominent key step involved a Diels-Alder intramolecular cyclization/dehydro-aromatization sequence. From these carbazole-lactam cores, linear syntheses have been developed for ellipticines and calothrixin B.
