ABSTRACT
A panel of novel ellipticine isomers were designed and synthesised with the aim of evaluating their anti-cancer effects on selected leukaemia cell lines. A preliminary NCI 60-cell screen demonstrated that these compounds display promising anti-tumour activity across a number of different cell types. We have consequently examined the effect of these derivatives in detail on the Acute Myeloid Leukaemia (AML) cell line, MV4-11. Cell cycle analyses revealed that the compounds had a range of distinctive cell cycle effects. 7-Hydroxyisoellipticine showed the most promise with respect to cytostatic activity. We demonstrated that this compound inhibited proliferation of leukaemia cells by preventing cells from progressing from G2 phase into mitosis over a period of 24 h at a concentration of 5 µM. Our research suggests that this is mediated by an induction of reactive oxygen species (ROS), which in turn activates the DNA damage response pathway. As a result of the activation of p53, cyclin B1 is inhibited. The induction of this pathway leads to apoptosis which is seen at 48 h using the same dose of 7-hydroxyisoellipticine. This study provides for the first time detailed cellular information on the potential use of isoellipticines as chemotherapeutic agents.
Subject(s)
Antineoplastic Agents/pharmacology , Cytostatic Agents/pharmacology , Ellipticines/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Reactive Oxygen Species/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
Reactive oxygen species (ROS) play an essential role in facilitating signal transduction processes within the cell. However, the precise details of the redox dynamics involved are not well understood. The generation of ROS is tightly controlled both spatially and temporally within the cell, making the study of ROS dynamics particularly difficult. In order to measure these dynamics, precise tools that can specifically examine the relevant ROS are required. Recent advancements in methodologies for ROS measurement have allowed the study of ROS biology at a level of precision previously unachievable. Here, we discuss improvements to fluorescent ROS dye technologies, genetically encoded ROS reporters, nanoparticle delivery systems, and nanotube ROS probes. These technologies improve specificity, localization and sensitivity over previously available ROS probes.
