**5. Cancer therapy and mitochondrial damage**

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; Rasumssen & Rasmussen, 1985).

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

Nutritional Supplements for Cancer-Associated Fatigue and

Cortes et al., 1978) and children (Iarussi et al., 1994; Loke et al., 2006).

et al., 1997; Cortes et al., 1978; Iarussi et al., 1994; Loke et al., 2006).

Nicolson & Conklin, 2008).

2004; Zee & Acoli-Isreal, 2009).

Cancer Therapy – A Molecular Basis for Restoring Mitochondrial Function 153

During chemotherapy of cancer, patients have received concurrent administration of CoQ10. This can affect both acute and chronic cardiotoxicity caused by anthracyclines (Conklin, 2004; 2005; Nicolson & Conklin, 2008). For example, Judy et al. (1984) studied the importance of administering CoQ10 on the development of doxorubicin-induced cardiotoxicity in patients with lung cancer. Doxorubicin given alone without CoQ10 caused marked impairment of cardiac function with a significant increase in heart rate and a substantial decrease in ejection fraction, stroke index and cardiac index. In contrast, doxorubicin administered along with CoQ10, did not cause cardiotoxicity—cardiac function remained unchanged. Other studies have confirmed these results and have shown that CoQ10 can reduce the cardiac toxicity of doxorubicin in adults (Buckingham et al., 1997;

Thus in preclinical and clinical studies the data indicate that CoQ10 protects the heart from the cardiotoxicity of anthracyclines. The impact of CoQ10 on the anti-neoplastic efficacy of anthracycline-based chemotherapy, however, was not studied in these reports (Buckingham

The most common complaint of patients undergoing anti-neoplastic therapy is fatigue, but there are also other complaints that include: pain, nausea, vomiting, malaise, diarrhea, headaches, rashes and infections (Buckingham et al., 1997; Loke et al., 2006; Manzullo & Escalante, 2002). Other more serious problems can also occur, such as cardiomyopathy, peripheral neuropathy, hepatotoxicity, pulmonary fibrosis, mucositis and other effects (Buckingham et al., 1997; Liu et al., 2005; Loke et al., 2006; Manzullo & Escalante, 2002). Due to misconceptions among patients and their physicians, most patients feel that cancer therapy-associated fatigue is an untreatable symptom (Vogelzang et al., 1997). Although fatigue is usually the most commonly reported adverse symptom during cancer therapy, up until recently there was little effort directed at reducing fatigue before, during or after cancer therapy (Von Roenn & Paice, 2005). This has changed recently (Nicolson, 2010;

Reducing cancer-associated fatigue and fatigue associated with cancer therapy are now considered important therapeutic goals. Psychological, physical, pharmaceutical and nutraceutical methods have been undertaken to reduce fatigue and improve the quality of life of cancer patients (Borneman et al., 2007; Escalante et al., 2011; Nicolson, 2010). These treatments are based on suppressing fatigue but also on controlling co-morbid or related symptoms, such as pain, anemia, cachexia, sleep disorders, depression and other symptoms (Escalante et al., 2011; Mustian et al., 2007; Nicolson, 2010; Ryan et al., 2007; Watson & Mock,

Unfortunately, there is no standard protocol related to treating cancer-associated fatigue and related symptoms. In reviewing the types of supportive measures used to control fatigue and related symptoms, the data suggest that graded exercise, nutritional support, treatment of psychological problems (such as depression with certain anti-depressants or psycostimulants), treatment of anemia with hematopoetic growth factors and control of insomnia with cognitive behavioral therapy or pharmacological and nonpharmacological therapies all have a role to various degrees in controlling cancer-associated fatigue

**7. Cancer-associated fatigue and other cancer-associated conditions** 

location they can displace CoQ10 from the electron transport chain (Conklin, 2005; Davies & Doroshow, 1986).

The displacement of CoQ10 from the electron transport chain during doxorubicin treatment results in decreases of CoQ10 in cardiac muscle (Karlsson et al., 1986) as the plasma concentration of CoQ10 increases (Eaton et al., 2000). CoQ10 normally accepts electrons from Complexes I and II and transfers them down the electron transport chain, resulting in the formation of water. However, the presence of aglycones in the inner mitochondrial membrane and inner matrix results in the transfer the electrons directly to molecular oxygen, resulting in the formation of superoxide radicals (Papadopoulou & Tsiftsoglou, 1996). Thus, doxorubicin generates a high level of oxidative stress in cardiac mitochondria, causing acute cardiac toxicity and damage to mitochondrial DNA (Conklin, 2005; Doroshow & Davies, 1986; Palmeira et al., 1991).

Anthracycline-damaged cardiac cell mitochondria cannot sustain their function, and changes in their structure results in disruption of mitochondria and eventually apoptosis (Serrano et al., 1999; Conklin, 2005; Gille & Nohl, 1997). This produces cardiac insufficiency and an inability to respond to pharmacological interventions, resulting ultimately in cardiac failure. However, if CoQ10 is administered during anthracycline chemotherapy, damage to the heart is prevented by decreasing anthracycline metabolism within cardiac mitochondria and by competing with aglycones for the CoQ10 sites within the electron transport chain (Conklin, 2005). Thus, CoQ10 administered concurrently with anthracyclines can maintain the integrity of cardiac mitochondria and prevent damage to the heart, and at the same time enhancing the anti-cancer activity of anthracyclines (Conklin, 2000; 2005).

In addition to chemotherapy, radiotherapy also produces damage to tissues other than cancerous tissues. Agents that protect tissues against radiation effects have been used to reduce unwanted damage (Brizel, 2007; Sabbarova & Kanai, 2007).

Radioprotective agents that have been used to decrease the adverse effects of radiotherapy are: antioxidants, free radical scavengers, inhibitors of nitric oxide synthase and antiinflammatory and immunomodulatory agents (Brizel, 2007; Sabbarova & Kanai, 2007). The most effective of these under development target mitochondria, such as proteins and peptides that can be transported into mitochondria and plasmids or nucleotide sequences, for example, agents that target and stimulate mitochondrial manganese superoxide dismutase genes to produce this important dismutase have been used as radioprotective agents (Sabbarova & Kanai, 2007).

### **6. Molecular replacement of mitochondrial components during cancer therapy**

As discussed in Section 5, chemotherapy can displace important mitochondrial cofactors, such as CoQ10 (Conklin, 2000; 2005). During chemotherapy replacement of CoQ10 dramatically prevents development of anthracycline-induced cardiomyopathy and histopathological changes. It can also prevent changes in electrocardiograms (EKG) characteristic of anthracycline-induced heart damage (Domae et al., 1981). Indeed, the administration of CoQ10 to animals resulted in increased survival, improvement in the EKG patterns, and reduced heart histopathological changes (Usui et al., 1982). These preclinical data, along with clinical data (discussed in Conklin, 2004 and Nicolson & Conklin, 2008) support the contention that CoQ10 protects the heart tssue from anthracycline-induced damage.

location they can displace CoQ10 from the electron transport chain (Conklin, 2005; Davies &

The displacement of CoQ10 from the electron transport chain during doxorubicin treatment results in decreases of CoQ10 in cardiac muscle (Karlsson et al., 1986) as the plasma concentration of CoQ10 increases (Eaton et al., 2000). CoQ10 normally accepts electrons from Complexes I and II and transfers them down the electron transport chain, resulting in the formation of water. However, the presence of aglycones in the inner mitochondrial membrane and inner matrix results in the transfer the electrons directly to molecular oxygen, resulting in the formation of superoxide radicals (Papadopoulou & Tsiftsoglou, 1996). Thus, doxorubicin generates a high level of oxidative stress in cardiac mitochondria, causing acute cardiac toxicity and damage to mitochondrial DNA (Conklin, 2005; Doroshow

Anthracycline-damaged cardiac cell mitochondria cannot sustain their function, and changes in their structure results in disruption of mitochondria and eventually apoptosis (Serrano et al., 1999; Conklin, 2005; Gille & Nohl, 1997). This produces cardiac insufficiency and an inability to respond to pharmacological interventions, resulting ultimately in cardiac failure. However, if CoQ10 is administered during anthracycline chemotherapy, damage to the heart is prevented by decreasing anthracycline metabolism within cardiac mitochondria and by competing with aglycones for the CoQ10 sites within the electron transport chain (Conklin, 2005). Thus, CoQ10 administered concurrently with anthracyclines can maintain the integrity of cardiac mitochondria and prevent damage to the heart, and at the same time

In addition to chemotherapy, radiotherapy also produces damage to tissues other than cancerous tissues. Agents that protect tissues against radiation effects have been used to

Radioprotective agents that have been used to decrease the adverse effects of radiotherapy are: antioxidants, free radical scavengers, inhibitors of nitric oxide synthase and antiinflammatory and immunomodulatory agents (Brizel, 2007; Sabbarova & Kanai, 2007). The most effective of these under development target mitochondria, such as proteins and peptides that can be transported into mitochondria and plasmids or nucleotide sequences, for example, agents that target and stimulate mitochondrial manganese superoxide dismutase genes to produce this important dismutase have been used as radioprotective

**6. Molecular replacement of mitochondrial components during cancer** 

As discussed in Section 5, chemotherapy can displace important mitochondrial cofactors, such as CoQ10 (Conklin, 2000; 2005). During chemotherapy replacement of CoQ10 dramatically prevents development of anthracycline-induced cardiomyopathy and histopathological changes. It can also prevent changes in electrocardiograms (EKG) characteristic of anthracycline-induced heart damage (Domae et al., 1981). Indeed, the administration of CoQ10 to animals resulted in increased survival, improvement in the EKG patterns, and reduced heart histopathological changes (Usui et al., 1982). These preclinical data, along with clinical data (discussed in Conklin, 2004 and Nicolson & Conklin, 2008) support the contention that CoQ10 protects the heart tssue from anthracycline-induced

enhancing the anti-cancer activity of anthracyclines (Conklin, 2000; 2005).

reduce unwanted damage (Brizel, 2007; Sabbarova & Kanai, 2007).

Doroshow, 1986).

& Davies, 1986; Palmeira et al., 1991).

agents (Sabbarova & Kanai, 2007).

**therapy** 

damage.

During chemotherapy of cancer, patients have received concurrent administration of CoQ10. This can affect both acute and chronic cardiotoxicity caused by anthracyclines (Conklin, 2004; 2005; Nicolson & Conklin, 2008). For example, Judy et al. (1984) studied the importance of administering CoQ10 on the development of doxorubicin-induced cardiotoxicity in patients with lung cancer. Doxorubicin given alone without CoQ10 caused marked impairment of cardiac function with a significant increase in heart rate and a substantial decrease in ejection fraction, stroke index and cardiac index. In contrast, doxorubicin administered along with CoQ10, did not cause cardiotoxicity—cardiac function remained unchanged. Other studies have confirmed these results and have shown that CoQ10 can reduce the cardiac toxicity of doxorubicin in adults (Buckingham et al., 1997; Cortes et al., 1978) and children (Iarussi et al., 1994; Loke et al., 2006).

Thus in preclinical and clinical studies the data indicate that CoQ10 protects the heart from the cardiotoxicity of anthracyclines. The impact of CoQ10 on the anti-neoplastic efficacy of anthracycline-based chemotherapy, however, was not studied in these reports (Buckingham et al., 1997; Cortes et al., 1978; Iarussi et al., 1994; Loke et al., 2006).
