**3. Oxidative stress and damage to mitochondrial membranes – Relationship to fatigue**

Another phenomenon associated with cancer and its progression as well as aging and agerelated degenerative diseases is oxidative stress (Dreher & Junod,1996; Halliwell, 1996; Kehrer, 1993). Oxidative stress is caused by an intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants. When this imbalance occurs, it results in oxidation of cellular structures, such as membrane lipids and proteins, and mutation of mitochondrial and nuclear DNA (Abidi & Ali, 1999; Bartsch & Nair, 2004; Marnett, 2000; Stadtman, 2002). ROS and RNS are naturally occurring cellular free radical oxidants that are usually present in low concentrations and are involved in gene expression, intracellular signaling, cell proliferation, antimicrobial defense and other normal cellular processes (Castro & Freeman, 2001; Ghaffari, 2008; Johnson et al., 1996). However, when ROS/RNS are in excess over cellular antioxidants, damage can occur to cellular structures (Abidi & Ali, 1999; Castro & Freeman, 2001; Ghaffari, 2008; Maes & Twisk, 2009). Recently Maes (2009) has proposed a link between excess oxidative stress (and activation of ROS/RNS pathways and fatigue and fatiguing illnesses.

Under normal physiological conditions our cellular antioxidant defenses usually maintain ROS/RNS at appropriate concentrations that prevent excess oxidation of cellular structures (Barber & Harris, 1994; Fridovich,1995; Sun, 1990). Endogenous cellular antioxidant defenses include glutathione peroxidase, catalase and superoxide dismutase, among other enzymes (Jagetia et al., 2003; Seifried et al., 2003), and low molecular weight dietary antioxidants (Aeschbach et al., 1994; Schwartz,1996). Some of these dietary antioxidants have been used as natural chemopreventive agents to shift the excess concentrations of oxidative molecules towards more physiological levels (Prasad et al., 200; Tanaka, 1994).

Excess oxidative stress (or primarily its mediators—excess ROS/RNS) within cancer cells has been linked to promotion and progression of malignancy of cancers (Brown & Bicknell, 2001; Klaunig & Kamendulis, 2004; Ray et al., 2000; Tas et al., 2005; Toyokuni et al., 1995). Thus oxidative stress and antioxidant status have been examined in various malignant cancers, such as breast (Brown & Bicknell, 2001; Kang, 2002; Ray et al., 2000; Tas et al., 2005), prostate (Aydin et al., 2006; Sikka, 2003), colorectal (Otamiri & Sjodahl,1989; Oxdemirler et al., 1989), renal (Asal et al., 1990; Gago-Dominguez et al., 2002), and other malignancies (Batcioglu et al., 2006; Manoharan et al., 2005; Seril et al., 2003). In all of these cancers ROS/RNS were in excess of antioxidant concentrations, resulting in cellular oxidative stress. Thus these cancers could possibly have been induced as a consequence of excess ROS/RNS and oxidative damage to the genetic apparatus (Abidi & Ali, 1999; Dreher & Junod, 1996; Jaruga et al., 1992). Even more likely than carcinogenesis is the promotion of progression of tumors that might not evolve to malignancy in the absence of excess oxidative stress (Nicolson, 2010; Nicolson & Conklin, 2008).

Nutritional Supplements for Cancer-Associated Fatigue and

**5. Cancer therapy and mitochondrial damage** 

Rasumssen & Rasmussen, 1985).

1998; Shacter et al., 2000).

2007).

Cancer Therapy – A Molecular Basis for Restoring Mitochondrial Function 151

Shacter et al., 2000). There are two major pathways of drug-induced apoptosis following cellular damage by antineoplastic agents: the mitochondrial pathway, initiated by release of cytochrome c, and the CD95 death receptor pathway, initiated by CD95L binding to its death receptor (Fojo, 2001). Oxidative stress during chemotherapy results in the generation of highly electrophilic aldehydes that have the ability to bind to the nucleophilic active sites of caspases as well as the extracellular domain of the CD95 death receptor. This inhibits caspase activity and the binding of CD96L ligand, and this results in the impairment of the ability of antineoplastic agents to initiate apoptosis (Chandra et al., 2000; Hampton et al.,

In addition to chemotherapy, radiotherapy also results in generation of oxidative stress and excess ROS/RNS (Feinendegen et al., 2007; Greenberger et al., 2001). The principal target of radiation is tumor cell DNA, and this can be directly damaged by radiation. However, genetic damage is also mediated by excess ROS/RNS (Epperly et al., 2003; Feinendegen et al., 2007). Recently the principal source of excess ROS/RNS during radiotherapy has been shown to be the mitochondria (Epperly et al., 2003; Sabbarova & Kanai, 2007). The initial cytotoxicity of radiation is now thought to be due to excess ROS/RNS triggering of apoptosis via alteration of mitochondrial metabolism. This causes transiently opening of mitochondrial permeability transition pores, which increases the influx of calcium ions into the matrix. The influx of calcium ions stimulates mitochondrial nitric oxide synthase and generation of nitric oxide, which inhibits the respiratory chain and eventually stimulates excess ROS/RNS free radicals that initiate apoptosis (Leach et al., 2002; Sabbarova & Kanai,

Cancer therapy is associated with several adverse side effects. One of the most difficult side effects is caused by chemotherapeutic drug damage to mitochondria (Conklin, 2000; Nicolson & Conklin, 2008). Cardiac mitochondria are especially sensitive to certain chemotherapy agents, such as anthracycline antibiotics (Conklin, 2004). Anthracyclineinduced cardiac toxicity is characterized by acute, reversible toxicity that causes electrocardiographic changes and depressed myocardial contractility and by chronic, irreversible, dose-related cardiomyopathy (Conklin, 2004; 2005). The selective anthracyclineinduced toxicity to cardiac cells is due to damage of cardiac mitochondria. The sensitivity of cardiac cells to anthracyclines, such as doxorubicin, has been found to be due to the unique properties of cardiac mitochondria in that they possess a Complex I-associated NADH dehydrogenase in the inner mitochondrial membrane facing the cytosol (Lehninger, 1951;

Doxorubicin is a relatively small molecule, and because of this property it readily penetrates the outer mitochondrial membrane. However, because it is hydrophilic and cannot partition into the lipid membrane matrix, it cannot penetrate the inner mitochondrial membrane (Conklin, 2005; Nohl, 1987). Thus, it cannot participate in oxidation-reduction reactions with the type of inner matrix-facing, electron transport chain dehydrogenases found in most types of cells, including most tumor cells (Conklin, 2005; Nohl, 1987). But in heart cells doxorubicin can interact with the mitochondrial cytosolic-facing NADH dehydrogenase that is unique to this tissue (Davies & Doroshow, 1986; Doroshow & Davies, 1986). This interaction produces doxorubicin aglycones, which are highly lipid soluble and readily penetrate the inner mitochondrial membrane (Conklin, 2005; Gille & Nohl, 1997). At this
