**9. Molecular replacement of oxidized membrane components and its effect on fatigue**

In cancer patients mitochondrial membranes as well as other cellular membranes are especially sensitive to oxidative damage by ROS/RNS, which occurs at high rates in cancer (Batcioglu et al., 2006; Dianzani, 1993; Gago-Dominguez et al., 2002; Manoharan et al., 2005; Otamiri & Sjodahl, 1989; Oxdemirler et al., 1989; Seril et al., 2003). Oxidation of membrane phospholipids alters their structure, affecting lipid fluidity, permeability and membrane function (Dianzani, 1993; Nicolson et al., 1977; Subczynski & Wisniewska, 2000). One of the most important events caused by ROS/RNS damage is loss of electron transport function, and this appears to be related to mitochondrial membrane lipid peroxidation. Membrane oxidation induces permeability changes in mitochondria, and this can cause loss of

(Escalante et al., 2011; Mustian et al., 2007; Nicolson, 2010; Ryan et al., 2007; Watson & Mock, 2004; Zee & Acoli-Isreal, 2009). Some of these approaches using pharmacological drugs and growth factors have been systematically analyzed in 27 studies (meta-analysis) by Milton et al. (2008). In this limited analysis, only a psycostimulant (methylphenidate) and hematopoetic growth factors (erythropoietin and darbopeitin) were more effective than placebo treatments. Other treatments were no better than placebo in the treatment of cancer-

**8. Cancer-associated fatigue, aging and oxidative mitochondrial damage** 

Cancer-associated fatigue has been defined as a multidimensional sensation (McDonald et al., 1993; Milton et al., 2008; Mustian et al., 2007; Ryan et al., 2007). Most patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion (Levy, 2008; Milton et al., 2008). Cancer-associated fatigue has been described as the dysregulation of several interrelated physiological, biochemical and psychological systems (Mustian et al., 2007; Ryan et al., 2007), but at the tissue and cellular levels fatigue is related to reductions in the efficiency of cellular energy systems, mainly found in mitochondria (Agadjanyan et al., 2003; Nicolson, 2003; 2005). Damage to mitochondrial components, mainly by ROS/RNS oxidation, can impair mitochondrial function, and this can also result in oxidative damage (reviewed in Bartsch & Nair, 2004; Castro & Freeman, 2001; Kehrer, 1993). Mitochondrial membranes and DNA are major targets of oxidative stress, and with aging ROS/RNS mitochondrial damage can accumulate (Huang & Manton, 2004; Wei &

During aging and in certain medical conditions oxidative damage to mitochondrial membranes impairs mitochondrial function (Huang & Manton, 2004; Logan & Wong, 2001; Wei & Lee, 2002). For example, in chronic fatigue syndrome patients there is evidence of oxidative damage to DNA and lipids (Logan & Wong, 2001; Manuel y Keenoy et al., 2001) as well as oxidized blood markers (Richards et al., 2000) and muscle membrane lipids (Felle et al., 2000) that are indicative of excess oxidative stress (Dianzani, 1993). In chronic fatigue syndrome patients also have sustained elevated levels of peroxynitrite due to excess nitric oxide, which can result in lipid peroxidation and loss of mitochondrial function as well as changes in cytokine levels that exert a positive feedback on nitric oxide production,

**9. Molecular replacement of oxidized membrane components and its effect** 

In cancer patients mitochondrial membranes as well as other cellular membranes are especially sensitive to oxidative damage by ROS/RNS, which occurs at high rates in cancer (Batcioglu et al., 2006; Dianzani, 1993; Gago-Dominguez et al., 2002; Manoharan et al., 2005; Otamiri & Sjodahl, 1989; Oxdemirler et al., 1989; Seril et al., 2003). Oxidation of membrane phospholipids alters their structure, affecting lipid fluidity, permeability and membrane function (Dianzani, 1993; Nicolson et al., 1977; Subczynski & Wisniewska, 2000). One of the most important events caused by ROS/RNS damage is loss of electron transport function, and this appears to be related to mitochondrial membrane lipid peroxidation. Membrane oxidation induces permeability changes in mitochondria, and this can cause loss of

related fatigue (Milton et al., 2008).

increasing the rate of membrane damage (Pall, 2000).

Lee, 2002).

**on fatigue** 

mitochondrial transmembrane potential, an essential requirement of oxidative phosphorylation (Kanno et al., 2004; Radi et al., 1994).

Lipid Replacement Therapy (Nicolson, 2003; 2005; 2010) has been used to reverse the accumulation of damaged lipids in mitochondria and other cellular membranes. Lipid Replacement Therapy plus antioxidants can reverse ROS/RNS damage and increase mitochondrial function in certain fatiguing disorders, such as chronic fatigue, chronic fatigue syndrome and fibromyalgia syndrome. Lipid Replacement Therapy has been found to be effective in preventing ROS/RNS-associated changes and reversing mitochondrial damage and loss of function (reviewed in Nicolson, 2010; Nicolson & Ellithrope, 2006).

Lipid Replacement Therapy with unoxidized lipid and antioxidant supplements has been effective in replacement of damaged cellular and mitochondrial membrane phospholipids and other lipids that are essential structural and functional components of all biological membranes (reviewed in Nicolson, 2010; Nicolson & Ellithrope, 2003). NTFactor, a Lipid Replacement oral supplement containing phospholipids, phosphoglycolipids, cardiolipid precursors and other membrane lipids, has been used successfully in animal and clinical lipid replacement studies (Agadjanyan et al., 2003; Ellithorpe et al., 2003; Nicolson & Ellithorpe, 2006; Nicolson et al., 2010). NTFactor's encapsulated lipids are protected from oxidation in the gut and can be absorbed and transported into tissues via lipid carriers without oxidation. Once inside cells the membrane lipids naturally replace oxidized, damaged membrane lipids by natural diffusion, and carrier proteins pick up the damaged lipids for degradation, transport and excretion (Mansbach & Dowell, 2000).

In preclinical studies NTFactor has been used to reduce age-related functional damage. Using rodents Seidman et al. (2002) found that NTFactor prevented hearing loss associated with aging and shifted the threshold hearing from 35-40 dB in control, aged rodents to 13-17 dB. They also found that NTFactor preserved cochlear mitochondrial function and prevented aging-related mitochondrial DNA deletions found in the cochlear. Thus NTFactor was successful in preventing age-associated hearing loss and reducing mitochondrial damage and DNA deletions in rodents (Seidman et al. 2002).

In clinical studies Lipid Replacement Therapy has been used to reduce fatigue and protect cellular and mitochondrial membranes from oxidative damage by ROS/RNS (reviewed in Nicolson, 2003; 2005; 2010). A vitamin supplement mixture containing NTFactor was by used by Ellithorpe et al. (2003) in a study of patients with severe chronic fatigue and was found to reduce their fatigue by approximately 40.5% in 8 weeks. In these studies fatigue was monitored by use of the Piper Fatigue Scale to measure clinical fatigue and quality of life (Piper et al., 1987). In addition, in a subsequent study we examined the effects of NTFactor on fatigue and mitochondrial function in patients with chronic fatigue (Agadjanyan et al., 2003). Oral administration of NTFactor for 12 weeks resulted in a 35.5% reduction in fatigue and 26.8% increase in mitochondrial function; whereas after a 12-week wash-out period fatigue increased and mitochondrial function decreased back towards control levels (Agadjanyan et al., 2003). Thus in fatigued subjects dietary Lipid Replacement Therapy can significantly improve and even restore mitochondrial function and significantly decrease fatigue. Similar findings were observed in chronic fatigue syndrome and fibromyalgia syndrome patients (Nicolson & Ellithorpe, 2003). Recently a new formulation of NTFactor plus vitamins, minerals and other supplements resulted in a 36.8% reduction in fatigue within one week (Nicolson et al., 2010) (Table 1).

Nutritional Supplements for Cancer-Associated Fatigue and

Table modified from Nicolson (2010).

restoring mitochondrial function.

cancer, *Cancer Letters* 142: 1-9.

**12. References** 

adverse effects reported by a research nurse.

cancers.

over trial.

Cancer Therapy – A Molecular Basis for Restoring Mitochondrial Function 157

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First arm Second arm improvement no change worsening \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\* The same regimen of 5-flurouracil/methotrexate/leukovoran was used for colon, pancreatic or rectal

#The percent of patients' self-reporting adverse effects was averaged with the percent of patients with

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Table 2. Effects of Propax with NTFactor on the adverse effects of chemotherapy in a cross-

Nutritional supplements have been used in a variety of diseases to provide patients with a natural, safe alternative to pharmacological drugs. In patients with cancer nutritional supplements are often used for specific purposes or to improve quality of life. For example, cancer-associated fatigue is one of the most common symptoms in all forms and stages of cancer, but few patients receive assistance for their fatigue. Cancer-associated fatigue is associated with cellular oxidative stress, and during cancer therapy excess drug-induced oxidative stress can cause a number of adverse effects, including: fatigue, nausea, vomiting and more serious effects. Cancer-associated fatigue and the adverse effects of cancer therapy can be reduced with Lipid Replacement Therapy, a natural lipid supplement formulation that replaces damaged membrane lipids along with providing antioxidants and enzymatic cofactors. Administering dietary Lipid Replacement Therapy can reduce oxidative membrane damage and restore mitochondrial and other cellular functions. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefits of specific Lipid Replacement Therapy nutritional lipid supplements in reducing fatigue and

Abidi, S. & Ali, A. (1999). Role of oxygen free radicals in the pathogenesis and etiology of

Aeschbach, R., Loliger, J., Scott, B. C., et al. (1994). Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol, *Food Chemistry and Toxicology* 32: 31-36. Agadjanyan, M., Vasilevko, V., Ghochikyan, A., et al. (2003). Nutritional supplement

Ahlberg, K., Ekman, T., Gaston-Johansson, F. & Mock, V. (2003). Assessment and management of cancer-related fatigue in adults*, The Lancet* 362 (9384): 640–650.

in aged subjects, *Journal of Chronic Fatigue Syndrome* 11(3): 23-26.

(NTFactor) restores mitochondrial function and reduces moderately severe fatigue

placebo Propax(+NTFactor) 57 22 21

Propax(+NTFactor) placebo 70 6 24

Average % patients on test arm#

**11. Summary – Cancer-sssociated fatigue and its treatment** 


Table 1. Effects of dietary Lipid Replacement supplement NTFactor on Piper Fatigue Scale scores.
