Antiproliferative Effect of the Piperidine Nitroxide Tempol on Neoplastic and Nonneoplastic Mammalian Cell Lines

• Published in: Free radical biology & medicine Vol. 24; no. 6; pp. 913 - 923
• Main Authors: Gariboldi, Marzia B, Lucchi, Simona, Caserini, Claudia, Supino, Rosanna, Oliva, Cesare, Monti, Elena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.1998
• Subjects: Acetylcysteine - pharmacology; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Cell cycle; Cell Cycle - drug effects; Cell Division - drug effects; Cell Line; CHO Cells; Cricetinae; Cyclic N-Oxides - pharmacology; Cytotoxicity; DNA Fragmentation - drug effects; Drug Screening Assays, Antitumor; Electron Spin Resonance Spectroscopy; Female; Free radicals; Growth Inhibitors - pharmacology; Humans; Rats; Spin Labels; Tumor cells; Tumor Cells, Cultured; Cytotoxicity; Free radicals; Tumor cells; Cell cycle; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/S0891-5849(97)00372-9

The stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) is widely used as a probe in biophysical studies and as an antioxidant in several experimental models. The potential cytotoxic effects of TEMPOL were tested on a panel of human and rodent cell lines, and the nitroxide proved to be significantly more effective in inhibiting the growth 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 seems to be related to the reactivity of the nitroxyl group. This observation, together with the antagonistic effect of N-acetylcysteine, suggests an involvement of free radical-mediated processes. Cell cycle studies indicate a biphasic effect of TEMPOL, with a short-term accumulation 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 points to an apoptotic mode of cell death. In conclusion, our data suggest that, while the possible cytotoxic effects of TEMPOL should not be overlooked when using this compound as a biophysical probe or antioxidant, these same properties could be exploited as a novel approach to cancer chemotherapy, especially in tumor cells exhibiting unfavorable characteristics, such as a multidrug-resistant phenotype or loss of hormone receptors.