Mechanisms of Anti-Cancer Agents  Emphasis on Oxidative Stress and Electron Transfer

Peter      Kovacic; Jose   A.   Osuna Jr.

Abstract

A large body of evidence has accumulated indicating involvement of oxidative stress (OS) in the mode of action of various bioactive substances, including those of the immune system. The data for anticancer drugs (main and miscellaneous) are summarized herein. Although diverse origins pertain, reactive oxygen species (ROS) are frequently generated by redox cycling via electron transfer (ET) groups, such as quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products) and conjugated imines (or iminium species). We believe it is not coincidental that these functionalities are frequently found in anticancer agents or their metabolites. Generally, the ET moieties display reduction potentials in the physiologically active range. Often ROS are also implicated in more traditional rationales, namely, enzyme inhibition, membrane or DNA insult, and interference with DNA or protein synthesis. A multi-faceted approach to mechanism appears to be the most logical. Significantly, the unifying theme of ET-OS also applies to other drug categories, as well as to toxins, carcinogens, hormones, and enzymes. Since this theoretical framework aids in our understanding of drug action, it can serve as a useful tool in the design of more active and safer pharmaceuticals.

Keywords: anticancer agents, oxidative stress, electron transfer, reactive oxygen species ROS, protein synthesis, SAR, metabolism, generation, ROS, chronology, nitro aromatics, radiation, radiation sensitizers, nitroimidazoles, indolequinones, tirapazamine, miscellaneous agents, photodynamic agents, peroxides, enediynes, metals, arsenic compounds, cis Pt, bleomycin, quinones, metal chelators, anthracyclines, paclitaxel Taxol