Tyrosine Kinase Inhibitor AG126 Reduces 7-Ketocholesterol-Induced Cell Death by Suppressing Mitochondria-Mediated Apoptotic Process

Abstract

The preventive effect of tyrosine kinase inhibitor AG126 against the 7-ketocholesterol toxicity was investigated in relation to the mitochondria-mediated cell death process. 7-Ketocholesterol induced the nuclear damage, the mitochondrial membrane permeability changes, the formation of reactive oxygen species and the depletion of GSH, which leads to cell death in differentiated PC12 cells. Tyrphostin AG126 significantly attenuated the 7-ketocholesterol-induced decrease in cytosolic Bid and Bcl-2 levels, increase in cytosolic pro-apoptotic Bax levels, mitochondrial membrane potential loss, cytochrome c release and subsequent caspase-3 activation. The inhibitory effect of tyrphostin AG126 may be supported by the inhibitory effect on another oxysterol 25-hydroxycholesterol-induced cell death. The results show that tyrphostin AG126 may prevent the 7-ketocholesterol toxicity by suppressing the mitochondrial membrane permeability change that leads to the cytochrome c release and caspase-3 activation. The preventive effect seems to be associated with the inhibitory effect on the formation of reactive oxygen species and the depletion of GSH.

Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease

“…7β-OH causes re-arrangement of the liquid-ordered phase which results in the formation of lipid rafts (Wang et al, 2008; Mitomo et al, 2009); it is also a potent inhibitor of α protein kinase C, an enzyme critical for memory consolidation and synaptic plasticity that is implicated in AD (Nelson and Alkon, 2005). Another oxysterol that might derive from the autoxidation of cellular cholesterol released during neurodegeneration is 7α-OH, which appeared to be responsible for SH-SY5Y cell death (Kölsch et al, 2000); a further possibility is 7-K. 7-K has been shown to enhance mitochondrial dysfunction in the neuronal PC12 cell line, leading to cell death (Kim et al, 2006; Kim and Lee, 2010; Jang and Lee, 2011). It has also been reported that incorporation of 7-K to lipid raft domains of plasma membranes triggers apoptotic signaling; α-tochopherol (vitamin E) reduces the cytotoxicity of 7-K by inhibiting its distribution to the lipid raft domains (Berthier et al, 2004; Royer et al, 2009).…”

Oxysterols and Their Cellular Effectors

“…Ghelli et al [89] showed that in ECV304 cells treated with 7-KC no cytochrome c release was associated with the observed loss of cell viability. More mechanistic insight has been gained from recent studies: Kim and Lee [90] provided evidence that the tyrosine kinase inhibitor AG126 reduced 7-KC-induced cell death by suppressing mitochondrial permeability change, apparently via inhibition of ROS generation and GSH (glutathione) depletion. On the other hand, Gao et al [91] demonstrated that apoptosis of J774 macrophage induced by the oxysterol cholesterol secoaldehyde (3β-hydroxy-5-oxo-5,6-secocholestan-6-al) is mediated via the mitochondrial pathway but without involvement of ROS.…”

Tyrphostin AG126 modulates Toll-like receptor (TLR) activation-induced functions in microglia by protein tyrosine kinase (PTK) -dependent and -independent mechanisms

“…Recently, preventive effects of AG126 in 7-ketocholesterol (KCL) toxicity were investigated in relation to the mitochondria-mediated cell death process by Kim and Lee (2010). They could show that AG126 attenuated the 7-KCL-induced decrease in cytosolic Bid and Bcl-2 levels and that it increased cytosolic pro-apoptotic Bax levels.…”