Cancer and atherosclerosis are major causes of death in western societies. Deregulated cell death is common to both diseases, with significant contribution of inflammatory processes and oxidative stress. These two form a vicious cycle and regulate cell death pathways in either direction. This raises interest in antioxidative systems. The human enzymes paraoxonase-2 (PON2) and PON3 are intracellular enzymes with established antioxidative effects and protective functions against atherosclerosis. Underlying molecular mechanisms, however, remained elusive until recently. Novel findings revealed that both enzymes locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress. As a result, ROS-triggered mitochondrial apoptosis and cell death are reduced. From a cardiovascular standpoint, this is beneficial given that enhanced loss of vascular cells and macrophage death forms the basis for atherosclerotic plaque development. However, the same function has now been shown to raise chemotherapeutic resistance in several cancer cells. Intriguingly, PON2 as well as PON3 are frequently found upregulated in tumor samples. Here we review studies reporting PON2/PON3 deregulations in cancer, summarize most recent findings on their anti-oxidative and antiapoptotic mechanisms, and discuss how this could be used in putative future therapies to target atherosclerosis and cancer. 1. Introduction Most studies in the field of paraoxonases (PONs) deal with cardiovascular diseases, such as atherosclerosis and diabetes, where PONs exert protective functions in cell culture as well as animal studies. It has been anticipated that the known antioxidative functions of PONs, including PON2 and PON3, were central to their effects although underlying molecular mechanisms remained obscure. However, recent findings caused a significant progress in this field because molecular pathways of PON2 and PON3 functions have been largely revealed. Moreover, the result of the cell-protective function were shown to play a vital role in survival and stress resistance of cancer cells, along with the finding that numerous tumors overexpressed these enzymes. There, PON2 and PON3 appear to increase chemotherapeutic resistance and favor cell survival. In this review, we summarize the most recent findings and discuss the role of PON2/PON3 in atherosclerosis and cancer. A future perspective gives an outlook on how PONs may be targets of novel therapeutic approaches. 2. Altered Expression Levels of Paraoxonase Enzymes in Cancer It is established that oxidative stress
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