RRR-ALPHA-TOCOPHERYL SUCCINATE INHIBITS THE PROLIFERATION OF HUMAN PROSTATIC TUMOR-CELLS WITH DEFECTIVE CELL-CYCLE DIFFERENTIATION PATHWAYS

The RRR-alpha-tocopheryl succinate derivative of vitamin E, referred t o as vitamin E succinate (VES), inhibits the proliferation of three me tastatic human prostatic cancer cell lines, LNCaP, PC-3, and DU-145. L NCaP is a lymph node-derived androgen-sensitive prostate cell line; th ese cells are defective for response to transforming growth factor-bet a (TGF-beta) but are normal for cell cycle-related tumor suppressor ge nes: p53 and retinoblastoma (Rb). PC-3 is a bone marrow-derived androg en-insensitive prostate cell line; these cells are defective for both p53 alleles but normal for both Rb alleles. DU-145 is a brain-derived androgen-insensitive prostate cell line; these cells are defective for both p53 and both Rb alleles. VES at 5, 10, and 20 mu g/ml inhibited DNA synthesis in the three cell lines in a dose-dependent manner. Puri fied TGF-beta(1) at 1 ng/ml inhibited DNA synthesis of PC-3 cells with in 24-72 hours and DU-145 cells at 72 hours but did not inhibit DNA sy nthesis of LNCaP cells. Previous studies in our laboratory showed that VES growth-inhibited tumor cells secrete biologically active antiprol iferative factor TGF-beta s, suggesting that VES's mechanism of growth inhibition may involve the TGF-beta system of growth control. The sig nificance of the studies reported here is that VES can inhibit the pro liferation of 1) cells that have lost the ability to respond to TGF-be ta s (le., LNCaP), 2) cells that are defective for Rb and p53 (i.e., D U-145), and 3) cells that are defective for p53 (i.e., PC-3), critical cell cycle regulatory molecules. Taken together, these studies show t hat VES most likely inhibits the proliferation of tumor cells via mech anism(s) in addition to and independent of TGF-beta, as well as the fu nctional status of Rb and p53.