ANTIPROLIFERATIVE EFFECT OF THE PIPERIDINE NITROXIDE TEMPOL ON NEOPLASTIC AND NONNEOPLASTIC MAMMALIAN-CELL LINES

The stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-(TEMPOL) is widely used as a probe in biophysical studies and as an antioxidant in several experimental models. The potential cytotoxic effects of TE MPOL were tested on a panel of human and rodent cell lines, and the ni troxide proved to be significantly more effective in inhibiting the gr owth of neoplastic than nonneoplastic cell lines after a 96-h exposure . More detailed studies on MCF-7/WT cells indicate that at least 24 h are necessary for TEMPOL to induce irreversible cell damage, which see ms to be related to the reactivity of the nitroxyl group. This observa tion, together with the antagonistic effect of N-acetylcysteine, sugge sts an involvement of free radical-mediated processes. Cell cycle stud ies indicate a biphasic effect of TEMPOL, with a short-term accumulati on of the cells in the G(1) phase and a later increase in G(2)/M phase ; the pattern of DNA fragmentation observed in TEMPOL-treated cells po ints to an apoptotic mode of cell death. In conclusion, our data sugge st that, while the possible cytotoxic effects of TEMPOL should not be overlooked when using this compound as a biophysical probe or antioxid ant, these same properties could be exploited as a novel approach to c ancer chemotherapy, especially in tumor cells exhibiting unfavorable c haracteristics, such as a multidrug-resistant phenotype or loss of hor mone receptors. (C) 1998 Elsevier Science Inc.