lly GC base pairs. DOX can form DNA adducts, binds to DNA and topoisomerases and inhibits DNA replication and transcription. It promotes DNA double-strand breaks (DSBs) and the DNA damage prompts various responses, including cell cycle arrest and apoptosis, primarily via activation of p53 pathway but also independent of it, with beneficial, if tumor cells, or otherwise detrimental consequences. While toxic to the tumor cell, DOX is also toxic to all other cell types. The cardiotoxicity of the drug is the main and the most severe adverse effect, and the cardiomyopathies associated with DOX can eventually lead to heart failure. The formation of reactive oxygen species (ROS), impaired iron homeostasis and mitochondrial dysfunction are thought to underlie the cardiotoxicity of DOX. Although more than 50% of DOX is eliminated unchanged, the drug undergoes several types of transformation such as two- and one-electron reduction and to a smaller extent deglycosidation. Free radical generation is a feature of DOX metabolism. The drug can interact with iron and generate hydroxyl radical and with the iron-responsive elements (IRE) regions of mRNAs, it can impact on the function of iron regulatory proteins (IRPs) and disturb iron homeostasis. In addition, DOX localizes to mitochondria, forms adducts with mitochondrial DNA, interacts with cardiolipin - an essential component of inner mitochondrial membrane, and is capable of impacting on a number of proteins/enzymes important for mitochondrial function. Doxorubicin is also administered as a pegylated liposomal product.

DOX, as mentioned, intercalates between adjacent DNA base pairs and forms adducts, both in nuclear and mitochondrial DNA. However, the main mechanism of action is 'trapping' of topoisomerases, and selectively, the type II topoisomerases Top2a and Top2b. Opening of DNA duplex and separation of strands during replication and transcription, creates supercoiling, both positive and negative, which needs to be removed to prevent polymerase stalling or formation of abnormal nucleic acid structures, respectively. Topoisomerases remove supercoiling although, depending on the enzyme type, via different mechanisms. DOX 'traps' Top2a and Top2b in Top-DNA cleavage complexes, thus blocking the resealing of strands. As such it blocks transcription and DNA replication, the latter having a major impact on the rapidly growing cancer cell. In addition, DNA damage triggers a series or responses eventually triggering cell death. Autophagy is also triggered but its exact roles are somewhat controversial. Autophagy can provide nutrients in times of starvation, but under more sustained stress it can promote cell death. To see the ontology report for annotations, GViewer and download, click here

...(less)