Mitochondrial damage apoptosis initiation

Figure 6.17 The intracellular signaling leading to apoptosis initiated by mitochondrial damage, DNA damage, or stimulation of Fas or TNF-1 receptors. For full explanation see text.

Similar interactions have been observed with the CDK inhibitor flavopiridol. Initial studies demonstrated that flavopiridol interacted synergistically with TNF to induce apoptosis in lung cancer cells. Subsequently, it was shown that co-administration of TRAIL with flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis in other tumor cell types (Senderowicz 1999 Rosato et al. 2004). Given evidence that flavopiridol acts at least in part to induce apoptosis in tumor cells via induction of mitochondrial injury, it seems plausible to propose that the potent tu-moricidal effects of a regimen combining TRAIL with flavopiridol, as in the case of HDACIs, stems from simultaneous activation of the intrinsic and extrinsic apoptotic pathways. 

The sensitivity to ionizing radiation is maximal in those cells able to activate a co-ordinate program of cell death (apoptosis) primed by the radiation-induced oxidative stress. Albeit apoptosis is a nuclear event and radiation-induced DNA damage is probably the most relevant mechanism of initiation of apoptosis, the control of the execution phase (and sometime also the initiation) takes place at the mitochondrial level. Radioresistance occurs... 

As the power house of the cell, the mitochondrion is essential for energy metabolism. As the motor of cell death (1), this organelle is central to the initiation and regulation of apoptosis. In addition, mitochondria are critically involved in the modulation of intracellular calcium concentration and the mitochondrial respiratory chain is the major source of damaging reactive oxygen species. Mitochondria also play a crucial role in numerous catabolic and anabolic cellular pathways. 

ROS play a critical role in initiation of apoptosis through changes in mitochondrial permeability, andpoly(ADP-ribose) polymerase (PARP) activation. These processes provide additional mechanisms for oxidative damage in acute neural trauma and neurodegenerative diseases (Warner et al., 2004). PARP activation is accompanied by the depletion of nicotinamide adenine dinucleotide, NAD. Depletion of NAD leads to depletion of ATP, which in turn promotes neuronal cell death (Zhang etal., 1994 Ishikawaetal., 1999). 

NAPBQl is an electrophile and as such will cause oxidative damage to cellular nucleophiles. This in turn will initiate a cascade of free radicals to be formed with the consequential oxidative damage resulting from these events. In addition, inhibition of ATP synthetase will result in a decrease in cellular ATP concentrations, mitochondrial dysfimction and more free radical formation. Other workers have put forward alternative hypotheses to the above two, and these include disruption of calcium homeostasis, altered mitochondrial function, Kupffer cell activation, protein nitrosylation, activation of inflammatory mediators, damage to DNA and apoptosis to name but a few ... 

It was also observed earlier that G-quadruplex ligands indueed more rapid effects on cell growth than that initially expected for telomerase inhibition alone. Apoptosis and short-term response were observed with triazine derivatives (12459, 115405), telomestatin, and more recently with the pyridine dicarboxamide derivatives (307A, 360A). " Telomestatin induced the activation of ATM and Chk2 that corresponded to an activation of the DNA damage response. 12459 induced apoptosis through the mitochondrial pathway and also provoked the early activation of P53. ... 

Apoptosis (programmed cell death) is a genetically controlled cell suicide process that has an essential role for the maintenance of homeostasis and prevention of cancer and some other diseases substantially in all living cells [141], Apoptosis is an optional elimination method for irreversibly damaged cells. The two major pathways that initiate apoptosis are extrinsic (death receptor mediated) and intrinsic (mitochondrial mediated). In addition, mitogenic and stress-responsive pathways are involved in the regulation of apoptotic signaling [142],... 

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