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Cancer cells most of their ATP through glycolysis, even under aerobic conditions, and there was a correlation

between glycolytic ATP production and aggressiveness of the tumor cells. These cells could be eliminated through the inhibition of mitochondrial oxidative phosphorylation (e.g. by moderate doses of ionizing radiation), which would reduce the activity of these organelles below a threshold level critical for cell survival, whereas mitochondria in normal cells would still be able to produce enough ATP. The impact of mitochondrial activities on cellular physiology is not restricted to ATP production for metabolic demands. Mitochondria also produce reactive oxygen species (ROS), which are involved, in the regulation of many physiological processes, but which might also be harmful to the cell if produced excessively (Gogvadze et al, 2008). One of the main characteristics of cancer cells is their fast Proliferation; rapidly growing tumors easily become hypoxic owing to the inability of the local vasculature to supply an adequate amount of oxygen. Tumor cells can successfully escape hypoxiamediated death as a result of lowered expression or mutation of p53 the inability of mitochondria to provide enough ATP for cell survival under hypoxic conditions, tumor cells must upregulate the glycolytic pathway. This occurs by induction of hypoxia-inducible factor 1 (HIF-1). HIF-1 stimulates key steps of glycolysis, but regulates genes that control angiogenesis, cell survival and invasion. Activation of Akt triggers increases in cell size, enhanced glycolytic activity and metabolism, and cell survival, and is commonly observed in cancer cells. HIF-1 induction can also be triggered by the mitochondria themselves. When mitochondrial respiration in tumor cells is downregulated, accumulation of Krebs cycle substrates might serve as a signal for stimulation of glycolysis. Succinate accumulation in mitochondria results from inhibition of succinate dehydrogenase. Mutations in this enzyme are involved in familial predisposition to benign tumors; therefore, succinate dehydrogenase can be considered as a classical tumor suppressor. Defects in mitochondrial respiration cause enhanced levels of NADH, which can subsequently inactivate PTEN (phosphatase and tensin homologue; a lipid phosphatase that antagonizes PI3K function and therefore inhibits downstream signaling through Akt) through a redox modification mechanism (Gogvadze et al, 2008). Mitochondria consume less oxygen and their ATP production decreases. Tumor cells can become glycolytic as a result of suppression of mitochondrial energy production. Low mitochondrial contribution to cellular ATP production under aerobic conditions is not a prerogative of tumor cells only; it is also seen in a variety of fast-growing normal cells. HIF-1 suppresses mitochondrial function in tumor cells, suggesting that it modulates the reciprocal relationship between glycolysis and oxidative phosphorylation. The role p53, are the central regulator of the cellular stress response, can modulate the balance between the glycolytic pathway and mitochondrial oxidative phosphorylation. Mutation of p53 in tumors causes downregulation of mitochondrial respiration as a result of COX deficiency and a shift of cellular energy metabolism towards glycolysis. Expression of TIGAR lowered fructose-2,6-bisphosphate levels in cells, resulting in the inhibition of glycolysis, while stimulating NADPH generation through the pentose phosphate shunt. The hypoxic environment of proliferating tumor tissue facilitates ROS production. Cellular hypoxia and re-oxygenation are two essential elements of ischemiareperfusion injury, and massive production of ROS is normally observed during reoxygenation of hypoxic tissue (Gogvadze et al, 2008). Glycolytic shift in cancer cells is that molecular oxygen becomes unavailable in fastproliferating cells, and thus the mitochondria cannot function properly in ATP production. The high rate of glycolysis in most tumors not only compensates for mitochondrial dysfunction but

also is required to support tumor cell proliferation. Important consequence of the glycolytic shift in tumor cells is their acquired resistance to apoptotic cell death. Glycolytic shift makes tumor mitochondria less susceptible to permeabilization of the OMM and, hence, less susceptible to activation of the mitochondrial pathway of apoptosis. The balance between pro-apoptopic and anti-apoptotic proteins in the OMM is crucial for apoptosis induction, and it appears that in many tumors the mitochondrial apoptotic pathway is suppressed owing to a disproportion between anti-apoptotic and proapoptotic mediators, in favor of the former. An imbalance among cellular levels of Bcl-2 family proteins can also contribute to OMM stabilization indirectly (e.g. through binding ofBcl-2 to the voltage-dependentanion channel [VDAC] a protein located in the OMM and responsible for most of the metabolite fluxes between the cytosol and the mitochondria. Influx could possibly trigger the induction of mitochondrial permeability transition(MPT), another mechanism of OMM permeabilization due to opening of a non-specific pore in the inner mitochondrial membrane (IMM), commonly known as the MPT pore. MPT is followed by the influx of water and ions into the matrix, causing mitochondrial swelling, rupture of the OMM, and the release of intermembrane space proteins such as cytochrome c into the cytosol. Permeabilization of the OMM can also result from the opening of so-called mitochondrial apoptosis-induced channels (MACs). MACs provide specific pores in the OMM for the passage of intermembrane space proteins, in particular cytochrome c, into the cytosol. The permeability of MACs was also shown to be dependent on the presence of Bcl-2 family proteins. Oxidation of cardiolipin causes the dissociation of cytochrome c, which might provide a plausible explanation for the anti-apoptotic effects reported for multiple mitochondrial antioxidants enzymes (Gogvadze et al, 2008). Another factor contributing to the mitochondrial resistance against MPT induction in tumor cells is the altered expression profile of ANT, a key component of the pore complex. Hexokinase-I binding to VDAC, the overexpression of ANT2 in tumors might contribute to mitochondrial resistance to OMM permeabilization. Akt activation inhibited cytochrome c release from mitochondria and thereby prevented the activation of caspases. PI3K activation, Akt rapidly accumulates in mitochondria, where it resides in both the outer and inner membranes, as well as in the matrix. Active Akt might also affect the oligomerization of Bax, a prerequisite step in OMM permeabilization. Akt activation inhibited cytochrome c release from mitochondria and thereby prevented the activation of caspases. PI3K activation, Akt rapidly accumulates in mitochondria, where it resides in both the outer and inner membranes, as well as in the matrix. The dependence of tumor cells on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at selective inhibition of the glycolytic pathway. Among the effects of the ATP depletion were rapid dephosphorylation of the pro-apoptotic protein Bad, migration of Bax to the mitochondria, and massive cell death. Stimulation of mitochondrial activity and restoration of the mechanisms of ATP generation characteristic of non-malignant cells might be an efficient tool in anticancer strategy. Inhibition of LDH, or stimulation of PDH through the inhibition of PDK1, could be particularly useful in tumors with impaired mitochondrial bioenergetics. Combined strategies involving manipulation of both the glycolytic and the mitochondrial pathways might be useful tools in the elimination of cancer cells that would otherwise survive thanks to mitochondrial ATP production. The resistance of cancer cells to treatment is often associated with flaws in their apoptotic program. Mitochondria are promising targets for such an approach. Hence, agents that suppress mitochondrial respiration, or uncouple oxidative

phosphorylation, have been shown to provoke cell death, although such compounds fail to kill cells depleted of mitochondrial DNA and therefore lacking an intact respiratory chain. The proapoptotic effect of a- TOS has been linked to its interaction with complex II of the mitochondrial respiratory chain, stimulation of ROS production, and promotion of the translocation of Bax from the cytosol to the mitochondria, causing cytochrome c release and caspase activation. Modulation of cellular redox balance through pharmacological stimulation of ROS production and/or depletion of protective reducing metabolites can lead to oxidative stress, destabilization of mitochondria and induction of apoptosis. The success of a coordinated attack on cancer must be based on the concerted modulation of cellular energy metabolism, mitochondrial stability, and other mechanisms responsible for the resistance to apoptosis characteristic of tumor cells (Gogvadze et al, 2008) .