Abstract
α‐Lipoic acid is a naturally‐occurring co‐factor found in a number of multi‐enzyme complexes regulating metabolism. We report here that α‐lipoic acid induces hyperacetylation of histones in vivo and has differential effects on the growth and viability of normal versus transformed cell lines. The human tumor cell lines FaDu and Jurkat, as well as a Ki‐v‐Ras‐transformed Balb/c‐3T3 murine mesenchymal cell line, all initiated apoptosis following exposure to α‐lipoic acid. In contrast, treatment of non‐transformed cell lines with α‐lipoic acid resulted only in reversible cell cycle arrest in G~0~/G~1~. Treatment with butyrate, another short‐chain fatty acid, induced a G~0~/G~1~ arrest in both transformed and non‐transformed cell lines. α‐Lipoic acid caused a post‐translational elevation in the levels of the cyclin‐dependent kinase inhibitor p27^Kip1^. Studies using p27^Kip1^‐deficient MEF cells demonstrated that p27^Kip1^ was required for the α‐lipoic acid‐mediated cell cycle arrest. The mechanism of apoptosis was independent of Fas‐mediated signaling, as α‐lipoic acid‐treated Jurkat cell mutants deficient in Fas or FADD retained sensitivity to apoptosis. The differential selectivity of the pro‐apoptotic effects of α‐lipoic acid for transformed cells supports its potential use in the treatment of neoplastic disorders. © 2003 Wiley‐Liss, Inc.