RRR-alpha-tocopheryl succinate (vitamin E succinate, VES), a derivative of vitamin E, is a potent antitumor agent. Cellular events involved in VES-induced DNA synthesis arrest of human MDA-MB-435 breast cancer cells were studied. VES induces a dose- and time-dependent inhibition of DNA synthesis and a G0/G1 cell cycle arrest. VES induces expression of p21Waf1/Cip1 mRNA and protein, and antisense oligomers to p21 block VES-induced growth arrest. Evidence suggesting that VES modulates p21 expression in a transforming growth factor-beta (TGF-beta)-independent fashion includes failure of TGF-beta-neutralizing antibodies to block VES-induced DNA synthesis arrest or VES activation of a p21 promoter-regulated reporter gene; VES is not capable of inducing the translocation of green fluorescent protein-Smad2 into the nucleus and is not capable of stimulating a TGF-beta-dependent reporter gene, and VES induces growth inhibition and upregulates p21 mRNA levels in TGF-beta receptor-defective cells.