Role of Caspase-8 Activation in Mediating Vitamin E-Induced Apoptosis in Murine Mammary Cancer Cells

Abstract

The vitamin E family of compounds is divided into two subgroups, tocopherols and tocotrienols. However, tocotrienols display more potent apoptotic activity in mammary cancer cells. Although the mechanism(s) mediating tocotrienol-induced apoptosis is presently unknown, apoptosis is carried out by activation of initiator caspases (caspase-8 or -9) that subsequently activate effector caspases (caspase-3, -6, or -7). Studies were conducted to determine whether tocotrienol-induced apoptosis is mediated by activation of the caspase-8 and/or caspase-9 pathway. Highly malignant +SA mouse mammary epithelial cells were grown in culture and maintained on serum-free media. Treatment with tocotrienol-rich-fraction of palm oil (TRF) and g-tocotrienol, but not a-tocopherol, induced a dose-dependent decrease in +SA cell viability. TRF- and g-tocotrienol-induced cell death resulted from apoptosis, as determined by DNA fragmentation and positive TUNEL assay staining. Additional studies showed that treatment with 50 mM TRF or 20 mM g-tocotrienol increased intracellular activity and levels of processed caspase-8 and -3 but not caspase-9. Furthermore, treatment with specific caspase-8 or -3 inhibitors, but not caspase-9 inhibitor, completely blocked the tocotrienol-induced apoptosis in +SA cells. These findings demonstrate that tocotrienol-induced apoptosis in +SA mammary cancer cells is mediated through activation of the caspase-8 signaling pathway and is independent of caspase-9 activation.

γ-Tocotrienol Inhibits Nuclear Factor-κB Signaling Pathway through Inhibition of Receptor-interacting Protein and TAK1 Leading to Suppression of Antiapoptotic Gene Products and Potentiation of Apoptosis

“…Our data are in agreement with other published reports that tocotrienol is a superior molecule among the members of the family of vitamin E (88,92,93). Four different homologues of tocotrienols have been identified, viz.…”

The potential therapeutic role of Fenugreek saponin against Alzheimers disease: Evaluation of apoptotic and acetylcholinesterase inhibitory activities

“…It considered as the central function in caspase cascade regulation and induction of apoptosis (Shafi et al, 2009). It has been found that caspases are the most important molecules in the apoptotic process which they enhance the pathway of the apoptotic cascade (Shah et al, 2003). This pathway is starting with releasing the cytochrome-c from the mitochondrial cells which stimulate the procaspase-9 and caspase-3 expression (Shafi et al, 2009).…”

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

“…35 The anticancer effect of T3 was found to be mediated through antiproliferation, 16,36,37 induction of apoptosis, 38,39 cell cycle arrest, 13,40 antiangiogenesis 41 and antiinvasion. 18 More recently, c-T3, one of the four isoforms of T3, was reported to possess chemosensitizing effects, 17,18 which led us to speculate that c-T3 may be able to target the chemoresistant cancer stem-like cells.…”