**8. Modulation of metabolism**

Cancer cells are known to favor anaerobic metabolism, even when oxygen is present and is known as the "Warburg effect" [116, 117]. Aerobic glycolysis is known to decrease ATP yield as well as increase lactate production by cancer cells [116–118]. To compensate for this decrease in ATP, cancer cells significantly increase glucose uptake through upregulation of glucose receptors [40, 41, 118]. Increased lactate in cancer cells enhances lactic acidosis, which is significantly toxic to the surrounding tissues and can facilitate tumor growth through the stimulation of ECM degradation, angiogenesis, and metastasis [118]. Additionally, aerobic glycolysis in cancer cells activates HIF, an oxygen-sensitive transcription factor that plays an important role in initiation and maintenance of the oncogenic phenotype [118]. In this regard, HIF induces the expression of several glucose transporters and glycolysis enzymes as well as induces the expression of pyruvate dehydrogenate kinase (PDK), an enzyme that stimulates pyruvate entry into the mitochondria for oxidation [41, 118, 119]. Thus, shifting glucose metabolism in cancer cells from glycolysis to glucose oxidation may have therapeutic value [120]. Indeed, inhibiting PDK by dichloroacetate (DCA) has been reported to induce apoptosis in tumor cells and significantly decreased HIF-1α expression [40]. More importantly DCA is currently in the clinical use for the treatment of hereditary mitochondrial diseases as well as lactic acidosis [41, 121]. The use of DCA at a dose of 35 to 50 mg/kg decreased lactate levels by more than 60% [41, 122]. Dichloroacetate treatment has been shown to significantly induce apoptosis, through the stimulation of caspase-3 activity, in a dose-dependent manner in EOC cells as well as other cancers, such as glioblastoma, endometrial, prostate, and non-small cell lung cancers [40, 123]. Aerobic glycolysis is associated with resistance to apoptosis in cancer cells as many of the enzymes in the glycolysis process are known to modulate gene transcription of apoptotic proteins [40, 41, 69, 124]. Stimulation of pyruvate entry into the mitochondria by DCA, through activation of PDH and inhibition of PDK, is an ideal method to shift aerobic glycolysis to glucose oxidation as inhibiting aerobic glycolysis results in ATP depletion and necrosis, not apoptosis [41, 125].

this control is thought to contribute to tumorigenesis [101]. Others have also shown that inhibition of NAD(P)H oxidase induced apoptosis in cancer cells [102]. Continuous ROS production by the cell and the environment further induces the inhibition of phosphorylation of AKT and subsequent suppression of AKT-mediated phosphorylation of ASK1 on Ser-83, resulting in significant decrease in apoptosis [102–104]. Furthermore, paclitaxel, a chemotherapeutic agent used in the treatment of ovarian cancer and other cancers, induced apoptosis of ovarian cancer cells by negative regulation of AKT–ASK1 phosphorylation signaling [102–104]. On the other hand, activation of AKT by ROS provided protection against apoptosis [102–104].

Data from our laboratory clearly demonstrated that treatment of EOC cells with DPI, which inhibits ROS production mediated by NAD(P)H oxidase, significantly reduced SOD3 and HIF-1α mRNA and protein levels as early as 30 minutes after treatment with a concomitant increase in apoptosis [52]. The association between increased HIF-1α expression and decreased cellular apoptosis has also been demonstrated in lung and hepatoma cancer cells [94, 105]. Overexpression of HIF-1α is thought to decrease apoptosis by the upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-xL and down regulation of pro-apoptotic proteins, BAX and BAK [106]. Inhibition of HIF-1α by rapamycin increased apoptosis by decreasing the expression of apoptosis inhibitor Bcl-2 in ovarian cancer xenografts [107]. Additionally, inhibition of HIF-1α by rapamycin enhanced apoptosis through the inhibition of cell survival

or SOD-catalyzed reactions [108–110]. Hydrogen peroxide serves as the precursor of more toxic hydroxyl radicals and thus is extremely destructive to cells and tissues [109–111]. The expression of SOD3 was reported to increase in response to intrinsic oxidative stress in ovarian cancer cells [112]. It has been demonstrated that overexpression of the SOD3 gene significantly suppressed lung cancer metastasis as well as inhibited the growth of B16-F1 melanoma tumors in mice [113, 114]. However, in a somewhat controversial study, it has been shown that inhibition of SOD selectively induced apoptosis of leukemia and ovarian cancer cells [10]. Under hypoxic conditions, SOD3 is overexpressed and has been reported to significantly induce the expression of HIF-1α in tumors through unknown mechanisms however, steady

mechanism [107, 115]. Therefore, inhibition of NAD(P)H oxidase and the consequent reduc-

SOD3 levels. Thus, we conclude that lowering oxidative stress, possibly through the inhibi-

serve as a potential target for cancer therapy. This effect was attributed to the modulation of

Cancer cells are known to favor anaerobic metabolism, even when oxygen is present and is known as the "Warburg effect" [116, 117]. Aerobic glycolysis is known to decrease ATP yield as well as increase lactate production by cancer cells [116–118]. To compensate for this decrease in

key enzymes that are central to controlling the cellular redox balance.

●– is utilized to produce H2

●– and the stabilization of HIF-1α have been proposed to play a role in this

●–, induces apoptosis in ovarian cancer cells and may

●– levels may destabilize HIF-1α, and subsequently increase apoptosis by lowering

O2

by nonenzymatic

signals in several other cell lines [107].

92 Ovarian Cancer - From Pathogenesis to Treatment

tion of NAD(P)H oxidase-generated O2

**8. Modulation of metabolism**

state levels of O2

tion of O2

Most of the NAD(P)H oxidase-generated O2

An additional approach to induce apoptosis in cancer cells is through scavenging high levels of oxidants produced by cancer cells utilizing antioxidants [126]. Deficiency in SOD or inhibition of SOD enzyme activity causes accumulation of O2 •− which is the precursor for several toxic free radicals that are critical to the oncogenic process [127]. Elevated levels of oxidants and free radicals are also known to induce cellular senescence and necrosis, and thus can kill tumor cells [40, 128]. The precise effect of high levels of oxidants and free radicals in cancer cells will depend on the type of cells and tissues, the site of production, and the type and concentration of oxidants [13].
