Treatment of the budding yeast Saccharomyces cerevisiae with the lipid peroxidation product 4-HNE provokes a temporary cell cycle arrest in G1 phase.

The effects of 4-hydroxy-2-nonenal (HNE) on the cell division cycle were investigated in the yeast Saccharomyces cerevisiae. A short treatment with HNE at a concentration in the range of the IC50 value in S. cerevisiae SP-4 cells induced a significant increase in the proportion of G0/G1 cells at the expense of S-phase cells. A similar delay in cell cycle progression upon treatment with HNE has recently been shown for HL-60 neoplastic cells. Long-term exposure in a synchronized yeast culture resulted in a pronounced dose-dependent block between G0G1- and S-phase, probably at or close to a point in the cell cycle that has been designated as "START." Incorporation of radioactively labeled precursors of macromolecules revealed that DNA synthesis was most susceptible to HNE in comparison to RNA and protein synthesis. Production of glutathione appeared to be required for the continuation of the cell cycle. HNE-treated yeast cells reentered the cell cycle when their glutathione content exceeded about twice the level of control cells. The release from the cell division cycle delay was followed by an enhanced growth to an extent that HNE-treated cells exceeded the number of control cells. These results indicate that HNE causes a biphasic modulation of cell proliferation. It was concluded that this effect was conserved during evolution from yeast to mammalian cells, emphasizing once more the usefulness of this unicellular organism as a model system for the investigation of the effects of free radical-derived products on the proliferation of eukaryotes.

Inhibition of melanoma B16-F10 growth by lipid peroxidation product 4-hydroxynonenal.

Since a gradual benign-to-malignant progression of murine melanoma B16 after exposure in vitro to hypoxia was described recently, the aim of this study was to test if exposing melanoma B16-F10 cells to aldehyde 4-hydroxynonenal (HNE), which is considered not only as one of the major "second toxic messengers" of oxygen free radicals (or oxidative stress), but as a normal constituent of many cells and tissues, might have opposite effects. Treatment of the tumor cells with 50 microM HNE in vitro or in vivo did not prevent development of the tumors, but inhibited their growth. Tumor growth inhibition was equal for in vitro and in vivo treatment, but appeared after a delay of almost one week, since there was no difference of the tumor volume to the control observed during the initial period of the tumor growth. Similarly, both HNE treatment of the tumor cells before transplantation and HNE treatment of the melanoma bearing mice resulted in equally prolonged survival time. Thus, the results obtained suggest that while hypoxia could increase the malignancy of the murine melanoma cells, exposing these cells to one of the major "second toxic messengers" of oxygen free radicals, HNE, has almost opposite effects and further indicate the possible use of the aldehyde in vivo.