Apoptosis Provoked by the Oxidative Stress Inducer Menadione (Vitamin K3) Is Mediated by the Fas/Fas Ligand System

Menadione, or vitamin K3 (VK3), a potent oxidative stress inducer, has been recently used as an effective and remarkably safe cytotoxic drug for treatment of several human tumors. VK3 induces apoptotic cell death through a poorly understood mechanism. Here we show for the first time that VK3-induced apoptosis requires the Fas/FasL system. Spleen cells from both Fas- and FasL-deficient mice (C57BL/6-lpr and C57BL/6-gld, respectively) had much lower levels of VK3 apoptosis in vitro compared to cells from control C57BL/6 mice. VK3 cytotoxicity toward mouse splenocytes was also blocked with a Fas-Fc fusion protein. VK3 induced apoptosis in Jurkat cells, coincident with an increase in both Fas and FasL expression. A FasL-resistant variant of these Jurkat cells was also resistant to VK3-induced apoptosis. Furthermore, because VK3 effects were inhibited by glutathione, a potent antioxidant, oxidative stress was linked to the Fas/FasL system. Moreover, since the Jurkat cell lines were p53 null, the activation of Fas/FasL system after oxidative stress apparently acted through a p53-independent pathway. The therapeutic relevance of the K vitamins has been growing in recent years; our findings offer new insight for improving and expanding their applications.