The Mechanisms of Isothiocyanate Induced Apoptosis in Mammalian Cell

ITC-induced apoptosis has been described on only a few occasions in the literature. This pathway is summarized in Figure 5. From the available data, both extracellular signalling and the mitochondrial death pathways have been

Figure 5 The apoptotic cascade initiated by isothiocyanates. Apafl, apopto-sis-associated factor 1; FADD, Fas-associated death domain; GSH, glutathione; MMP, mitochondrial membrane potential; ROS, reactive oxygen species. (Adapted from Refs. 166-173.)

implicated in ITC-induced apoptosis, and an overview is given below. Cancerous cells often enter cell cycle arrest when exposed to physiological concentrations of ITCs. However, at high concentrations apoptosis may occur as determined by morphological changes. For instance, AITC, BITC, and PEITC constituents of many cruciferous vegetables can inhibit cancer cell differentiation and induce selective toxicity in the human colorectal HT29 tumor cell line (163-165).

Additional data have also demonstrated G2/M-phase cell cycle arrest and apoptosis induced by sulforaphane in HT29 colon cancer cells in vitro (166). Of all the ITCs studied PEITC has received the most attention as to its role in inducing apoptosis in vitro. The time- and dose-dependent induction of apoptosis with significant increase in caspase-3-like activity has been demonstrated in HeLa cells treated with PEITC (167). This work was subsequently followed by the publications of Xu and Thornalley, who highlighted the role of caspase-8, JNK1, and Bid cleavage in human HL60 leukemia cells exposed to PEITC (168,169). The role of JNK in PEITC-induced apoptosis has also been the main focus of research for Chen and colleagues. They first demonstrated that JNK activation was important in PEITC-induced apoptosis and later showed that the transient increase in JNK activity was due to inhibition of JNK degradation by PEITC (170).

Additional studies have also suggested a role of p53 in the apoptotic cascade induced by PEITC in mouse epidemermal JB6 cells. The increased expression of p53 and the inability of PEITC to induce apoptosis in p53-deficient mouse embryonic fibroblast suggested a significant role of p53 in the induction of apoptosis (171). However, later work by Xu and Thornalley and, more recently, Xiao and Singh has shown apoptosis can occur in p53-deficient cells. Indeed, Xiao and Singh observed a role of the extracellular signaling kinases ERK 1 and 2 in PEITC-induced apoptosis in human prostate PC-3 cells (172). Inhibition of the ERK-signalling cascade prevented PEITC-induced apoptosis. In addition to extracellular signaling, the mitochondrial death pathway has been implicated in ITC-induced apoptosis. Nakamura et al. described the loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 in BITC-induced apoptosis in the hepatic RL60 cell line. Associated with the loss of MMP was a dose-dependent increase in the levels of reactive oxygen species (ROS), derived from the mitochondrial electron transport chain (173). However, what role ROS has in ITC-induced apoptosis has not been determined. Investigations in our laboratory also implicate a mitochondrial death pathway in PEITC-induced apoptosis in hepatoma HepG2 cells. PEITC is observed to cause a rapid loss of cellular GSH followed by a significant decrease in mitochondrial membrane potential, cytochrome c release, and activation of caspase-3 and caspase-9 (P. Rose, unpublished observations).

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