Yeasts, such as Saccharomyces cerevisiae, have long served as useful models for the study of oxidative stress, an event associated with cell death and severe human pathologies. This review will discuss oxidative stress in yeast, in terms of sources of reactive oxygen species (ROS), their molecular targets, and the metabolic responses elicited by cellular ROS accumulation. Responses of yeast to accumulated ROS include upregulation of antioxidants mediated by complex transcriptional changes, activation of pro-survival pathways such as mitophagy, and programmed cell death (PCD) which, apart from apoptosis, includes pathways such as autophagy and necrosis, a form of cell death long considered accidental and uncoordinated. The role of ROS in yeast aging will also be discussed.

Regulation of the cell cycle and apoptosis are two eukaryotic processes required to ensure maintenance of genomic integrity, especially in response to DNA damage. The ease with which yeast, amongst other eukaryotes, can switch from cellular proliferation to cell death may be the result of a common set of biochemical factors which play dual roles depending on the cell's physiological state. A wide variety of homologues are shared between different yeasts and metazoans and this conservation confirms their importance. This review gives an overview of key molecular players involved in yeast cell-cycle regulation, and those involved in mechanisms which are induced by cell-cycle dysregulation. One such mechanism is autophagy which, depending on the severity and type of DNA damage, may either contribute to the cell's survival or death. Cell-cycle dysregulation due to checkpoint deficiency leads to mitotic catastrophe which in turn leads to programmed cell death. Molecular players implicated in the yeast apoptotic pathway were shown to play important roles in the cell cycle. These include the metacaspase Yca1p, the caspase-like protein Esp1p, the cohesin subunit Mcd1p, as well as the inhibitor of apoptosis protein Bir1p. The roles of these molecular players are discussed.

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used to treat pain, fever, and inflammation. However, mounting evidence shows that NSAIDs, such as aspirin, have very promising antineoplastic properties. The chemopreventive, antiproliferative behaviour of NSAIDs has been associated with both their inactivation of cyclooxygenases (COX) and their ability to induce apoptosis via pathways that are largely COX-independent. In this review, the various proapoptotic pathways induced by traditional and novel NSAIDs such as phospho-NSAIDs, hydrogen sulfide-releasing NSAIDs and nitric oxide-releasing NSAIDs in mammalian cell lines are discussed, as well as the proapoptotic effects of NSAIDs on budding yeast which retains the hallmarks of mammalian apoptosis. The significance of these mechanisms in terms of the role of NSAIDs in effective cancer prevention is considered.

In previous studies, we observed that aspirin, a promising cancer-preventive agent, induces apoptosis in mitochondrial manganese superoxide dismutase (MnSOD)-deficient Saccharomyces cerevisiae cells grown aerobically in ethanol medium. In this study, we show that aspirin-induced apoptosis is associated with a significant increase in mitochondrial and cytosolic O2 ·- and oxidation of mitochondrial NAD(P)H. A concomitant rise in the level of cytosolic CuZnSOD activity failed to compensate for mitochondrial MnSOD deficiency. However, an observed increase in activity of Escherichia coli FeSOD targeted to the mitochondrial matrix of the MnSOD-deficient yeast cells, markedly decreased aspirin-induced accumulation of mitochondrial O2 ·-, significantly increased the mitochondrial NAD(P)H level and rescued the apoptotic phenotype. Indeed, recombinant yeast cells expressing E. coli FeSOD behaved in a similar manner to the parent wild-type yeast cells with native mitochondrial MnSOD activity. Wild-type cells consistently showed a decrease in mitochondrial O2 ·- and an increase in mitochondrial NAD(P)H levels in the presence of aspirin in ethanol medium. In fact, in wild-type cells, our studies supported an antioxidant action of aspirin. Taken together, our results indicate that a pro-oxidant effect of aspirin occurring predominantly in cells with compromised mitochondrial redox balance may be enough to overcome antioxidant defences resulting in apoptosis, as observed in MnSOD-deficient yeast cells.