Cancer induced cachexia (CIC)

Effective integrative management

Abstract

Cancer induced cachexia (CIC) is a syndrome of muscle wasting accompanied by anorexia with or without loss of adipose tissue. Underlying CIC is a complex interaction of proinflammatory cytokines that act centrally on the hypothalamus and peripherally to increase catabolism and resting energy expenditure, while decreasing protein synthesis. The presence of CIC is an important prognostic indicator in cancer patients. Nutritional strategies utilized by naturopathic doctors have been proven to slow down this condition, induce weight gain, and improve cancer related outcomes. Such therapies include high EPA fish oil, melatonin, L-carnitine, and branched chain amino acids and/ or whey protein.

Cancer induced cachexia (CIC) is a multifactorial syndrome characterized by loss of skeletal muscle, accompanied by anorexia and (sometimes) loss of adipose tissue (Fearon 2011). A number of underlying metabolic derangements are implicated in CIC, and associated symptoms may include malnutrition, anemia, fatigue, and decreased muscle strength & impaired physical function. Cachexia, defined as a loss of body weight greater than 5%, leads to poor performance, poor quality of life, increased complications, and higher mortality rate among cancer patients (Burckart 2010, Fearon 2011). Targeted nutritional interventions are an important part of cachexia prevention and management. This paper reviews several key agents that can improve outcomes in cachexia, among them fish derived omega-3 fatty acids (EPA and DHA), melatonin, branched chain amino acids (BCAAs), l-carnitine, and whey protein.

Cachexia is a therapeutic target of high importance in cancer patients due to its strong prognostic significance (Burckhart 2010). It is widely recognized that cachexia leads to poorer cancer outcomes, and is reported as the direct cause of death in up to 20-40% of cancer patients (Fox 2009). Recently, Yang et al found that, among a large cohort of lung cancer patients (n=14,751), those who showed weight loss (15.8% average) at time of diagnosis had significantly shorter survival time compared to those who did not, 6.4 versus 9.2 mo, P < 0.001 (2011). Similar results have been found for other cancers as well, including colorectal cancer and pancreatic cancer, with up to two fold greater increase in risk of death (HR = 2.26; CI 1.18-4.32; P = 0.014) reported (Bachmann 2008, Thoreson 2012). Some teams have used serum albumin as a marker of malnutrition and cachexia, and low levels have been associated with decreased survival in ovarian, breast, and other cancers (Asher 2011, Lis 2003, Polterauer 2010). Cancer related weight loss is associated with decreased tolerance to anticancer therapy, and significantly predicts toxicity from cancer treatment (Fearon 2011, Ross 2004). Naito found that cachexia is associated with altered oxycodone pharmacokinetics due to decreased albumin levels (an important drug binding and transporting protein), resulting in increased levels of free drug and increased incidence of central adverse reactions (2012). Despite this, cachexia remains under-recognized in patients, and under-treated as a clinical entity (Churm 2009, Spiro 2006).

The molecular mechanisms underlying CIC are still being elucidated, however, pro-inflammatory cytokines such as IL-1, IL-2, IL-6, interferon gamma and TNF α have a key role in mediating cancer cachexia (Macdonald 2003). IL-6 is a key cytokine in iniating multiple proinflammatory pathways including the acute phase response, and is known to be produced by the tumor microenvironment (Oshima 2012, Zamarron 2011). The inflammatory basis of CIC distinguishes it from age related sarcopenia or frank starvation (Pepersack 2011), and presents the therapeutic rationale for intervention with agents such as EPA, NSAIDS, and celecoxib, a COX-2 inhibitor. Ultimately, these pro-inflammatory cytokines initiate a cascade of events in the hypothalamus and peripherally that results in detrimental metabolic changes, including increased catabolism (proteolysis and lipolysis) and resting energy expenditure, reduced muscle protein synthesis, and anorexia (Burckart 2010). According to a more simple summation by Fearon, “The pathophysiology [of cachexia] is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism” (2011).

Various definitions of CIC have been used. Two recent sets of diagnostic criteria are outlined in Table 1. These criteria by Fearon are recently proposed in a consensus statement published in Lancet Oncology (2011), while those by Evans are older and incorporate biochemical parameters (2008). Recently, work has been done to establish staging of cachexia. Precachexia is defined as “weight loss ≤5%, with anorexia and metabolic changes” (Fearon 2011). Cachexia is as defined below (Fearon 2011). Refractory cachexia is variable in terms of severity, with the presence of procatabolic state; cancer not responsive to anticancer treatment; low performance score; and <3 months expected survival (Fearon 2011). A proposed algorithm in terms of assessment and management is adapted in Figure 1. (Valium)

Nutritional Interventions Fish Derived Omega-3 Fatty Acids

Fish oil is rich in the omega-3 polyunsaturated fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), and has been shown to suppress the production of proinflammatory cytokines in both healthy volunteers and cancer patients, leading to weight stabilization, improved immune function, and better cancer treatment outcomes (Barber 2001, Wigmore 2000). Evidence on use of EPA in various cancer types is summarized in Table 2.

A 2007 systematic review found that oral supplements enriched with omega-3 fatty acids increased weight gain, increased appetite, improved quality of life and reduced post-surgical morbidity in patients with advanced pancreatic and upper gastrointestinal cancer (Colomer 2007). Not all trials have shown such promising effects (Fearon 2006), however, though the reason may have to do with cancer stage, study duration, and differences between cancer types and phenotypes. Although the dosages used in clinical trials shows some variability, a dose of at least 2g EPA per day is recommended. No serious side effects have been reported in the trials reviewed; minor side effects typically include fishy aftertaste and mild nausea or GI symptoms.

Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is a chronobiological hormone secreted by the pineal gland that is responsible for maintaining circadian rhythms. Melatonin acts as a potent antioxidant, immune modulating agent, antitumor, and antitoxic agent with respect to reducing radiation and chemotherapy induced toxicity (Seely 2011, Vijayalaxmi 2002). A recent meta analysis by Seely et al including 21 RCTs showed that melatonin alongside chemo and/ or radiation therapy improves survival (reduction in one year mortality, RR = 0.60; 95% CI = 0.54-0.67) and decreases toxicities of treatment, including asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia (2011). Preliminary trials have shown an effect of melatonin on cachexia.

In a randomized controlled trial, 24 patients with advanced gastrointestinal cancer were randomized to receive fish oil or melatonin (Persson 2005). For the fish oil group, 13 patients received the equivalent of 4.9 g EPA and 3.2 g DHA/d, while the melatonin group (n=11) were given 18 mg melatonin/d. After four weeks, five of the 13 patients (38%) in the fish oil group and 3 of 11 patients (27%) in the melatonin group showed weight stabilization or gain. Notably, after combining both interventions, 63% of individuals responded, suggesting an additive effect from the combination.

In another study, Lissoni et al found that among 100 patients with untreatable metastatic solid tumours, those receiving supportive care plus melatonin (20 mg/day orally in the evening x2mo) versus supportive care alone showed slower weight loss and decrease in TNF levels: “The per cent of weight loss greater than 10% was significantly higher in patients treated by supportive care alone than in those concomitantly treated by MLT, with no difference in food intake (P < 0.01)” (1996).

Branched Chain Amino Acids

The branched chain amino acids consist of leucine, isoleucine, and valine, and these may act indirectly by modulating serotonin activity in the hypothalamus. In the brain, the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine are dependent upon the availability of the aromatic amino acids (tryptophan, phenylalanine, and tyrosine) respectively (Fernstrom 2005). Branched chain amino acids are thought to counteract the effects of anorexia by competing with tryptophan for entry through the blood brain barrier (Inui 2002). In cancer serotonin levels can be elevated as a result of increased plasma tryptophan. Through competition, BCAAs allow less serotonin in the brain, and result in a reduction in the amount of hypothalamic activity contributing to anorexia (Inui 2002). In addition BCAAs possess anabolic effects peripherally in skeletal muscle (Laviano 2005).

In a double blind prospective study, 28 cancer patients with anorexia were given an oral supplement consisting of branched chain amino acids 4.8 g three times daily for seven days (Le Bricon 1996). In the BCAA- treated group, the incidence of anorexia decreased from 100% to 45% by the end of the study. In the placebo group, the incidence of anorexia remained at 84%. The authors concluded that BCAA supplementation can safely be administered for the treatment of cancer-induced anorexia (Le Bricon 1996).

In a study of patients with intraabdominal adenocarcinoma and receiving total parenteral nutrition (TPN), the effects of a solution containing 19% BCAAs was compared to an isocaloric, isonitrogenous formula containing 50% BCAAs (Hunter 1989). In the high BCAA group, the following outcomes were observed in comparison to the low BCAA group: increase in whole body protein synthesis and breakdown (p<0.05); increased synthesis rate of albumin (P< 0.05); and reduction in tyrosine oxidation, suggesting improved protein utilization.

In terms of BCAA supplementation in increasing lean body mass, clinical trials have been inconsistent in elucidating its effects on skeletal muscle synthesis in humans (Choudry 2006). To date, trials have largely been small and variable and there is no clear positive or negative benefit to BCAA supplementation. The evidence regarding BCAA supplementation in severe catabolic patients is more encouraging. Studies regarding this particular patient population have used more objective outcome measures such as decreases in urinary nitrogen excretion to show benefits.

L-Carnitine

L-carnitine is an amino acid derivative and important cofactor in facilitating mitochondrial fatty acid metabolism within muscle tissue. L-carnitine is responsible for the transportation of fatty acids across the mitochondrial membrane in exchange for acetyl CoA, a byproduct of fatty acid oxidation (Fritz 2011). Maintaining this shuttle system 1. ensures substrate (fatty acids) for the production of ATP through beta oxidation in the mitochondria; and 2. prevents inhibition of glucose metabolism, which could happen through inhibition of pyruvate dehydrogenase by buildup of acetylCoA within the mitochondria (Fritz 2011). Some forms of chemotherapy have been shown to deplete carnitine, in part through impaired renal reabsorption (Hockenberry 2009, Mancinelli 2007). Open label studies of L-carnitine in cancer patients have shown improvements in lean body mass and fatigue (Gramignano 2005, Graziano 2002); RCTs of L-carnitine in combination with other agents in the treatment of cachexia have shown a superior combined effect on measure of cachexia, prognostic scores, and inflammatory cytokines (Maccio 2012, Mantanovi 2010).

Whey Protein Whey protein supplementation contributes to adequate protein intake, while supplying all the essential amino acids in order to maximize muscle protein synthetic activity and optimal immune function. Whey contains high concentrations of the BCAAs as well as beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin, lactoferrin, immunoglobulins, lactoperoxidase enzymes, glycomacropeptides, lactose, and minerals (AltMedRev 2008). Human evidence shows that whey protein is rapidly absorbed and can effectively stimulate muscle protein synthesis (FSR) (Deutz 2011).

Use of a high protein, high leucine whey formula was investigated in 25 cancer patients prior or after chemotherapy treatment (Deutz 2011). The whey group (n = 13) received a formula containing 40g of protein based on casein, whey, and free leucine, while the control group (n =12) was given 24g of casein alone. Results showed that the fractional rate of muscle protein synthesis (FSR) significantly increased from 0.073 (SD: 0.023) to 0.097 (SD: 0.033) (p = 0.0269) in the whey group but not in the control group, showing the superior effects of a whey and leucine containing protein supplement.

A small trial examining the effect of whey on cancer progression was conducted among seven patients with metastatic cancer (five breast, one liver, one pancreas) (Kennedy 1995). Whey protein was supplemented at 30g daily for six months. In six patients, baseline blood lymphocyte GSH (glutathione) levels were substantially elevated, according to authors, “reflecting high tumour GSH levels” (Kennedy 1995). After treatment with whey, two patients exhibited “signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal” (Kennedy 1995). Two patients showed tumour stabilization and increased haemoglobin levels. Three patients had disease progression. The authors conlcuded that “whey protein concentrate might deplete tumour cells of GSH and [thereby] render them more vulnerable to chemotherapy” (Kennedy 1995). In addition to effects on tumor cell levels of GSH, whey protein has been shown to possess anticancer activity in animals by increasing GSH concentration in healthy tissues, thereby stimulating immune function through the GSH pathway (Bounous 2000). Glutathione is depleted in conditions of immune deficiency, for example HIV and cachexia; under these circumstances, whey protein acts as a cysteine donor to replenish GSH, since cysteine is the crucial limiting amino acid for intracellular GSH synthesis (Bounous 2000).

Conclusion

Naturopathic interventions used for treatment in cancer cachexia are based on good human level evidence and may offer important advantages to cancer patients, particularly in combination. These include high EPA fish oil, melatonin, branched chain amino acids, L-carnitine, and whey protein supplementation. These agents have a good safety profile in that little or no interactions with chemotherapy have been observed in human trials. While evidence suggests benefit from the application of each of these nutrients in isolation, a much stronger impact can reasonably be anticipated from their combined application, thus targeting multiple pathways and factors underlying the pathophysiology of cancer cachexia.

Coauthor Reshi Mehta would like to thank Dr Kieran Cooley, Dr Douglas Andrews, and Dr Philip Rouchotas for their guidance in the compilation of this manuscript.

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Galectin-3
An emerging treatment target; role of MCP

Chronic illnesses such as cancer, cardiovascular disease, diabetes and others share common metabolic and inflammatory derangements. Novel epidemiological forecasts predict that a new category of diseases may soon be established, classifying these chronic illnesses as “Elevated Galectin-3 Diseases.”

Galectin-3 is a beta-galactoside binding lectin, ie, a carbohydrate binding protein with an affinity for beta-galactoside containing glycans (Iurisci 2000), expressed by epithelial and immune cells (Yu 2010). Several ligands for galectin-3 have been described, including lysosomal-associated membrane proteins 1 and 2, IgE, laminin & fibronectin, and Mac-2 BP (aka 90K) (Iurisci 2000, Yu 2010); and the biological function of galectin-3 is the subject of increasing research. Although the molecule is normally present in the body at relatively low concentrations, levels are greatly increased in a variety of chronic diseases, granting galectin-3 utility as a marker of disease risk and progression (Iurisci 2000). Notably, galectin-3 appears to be an active biomarker, as opposed to other surrogates such as C-reactive protein (CRP).

Galectin-3 has been shown to be involved in a large number of biological processes, including inflammation, proliferation, and fibrosis. In cardiovascular disease, it is implicated in mediating fibrosis (Lin 2009), while in cancer it appears to be active in promoting metastasis and angiogeneisis (Iurisci 2000). For instance, galectin-3 on the cell surface promotes interactions with glycans on adjacent cell surfaces, promoting tumor cell adhesion, invasion, and dissemination (Yu 2011). Conversely, suppression of galectin-3 expression in animal models results in reduced tumor growth and metastasis (Honjo 2001). Circulating galectin-3 may also play a role in the inhibition of anti-tumor T-cell activity (Peng 2008).

In 2011, the groundbreaking PREVEND study (Prevention of REnal and Vascular ENd-stage Disease) found that elevated serum galectin-3 predicted a two-fold increase in all cause mortality among the general population (deBoer 2011, 2012). A total of 7968 people were following for ten years, with overall mortality being 15.6% in the highest quintile, compared to 7.7% in the lowest quintile (De Boer 2011, 2012). For each standard deviation increase in galectin-3, there was a corresponding 46% increase risk in all cause mortality, HR 1.46 (95% CI 1.37-1.56, unadjusted), and this remained upon adjustment for age, gender, and classical risk factors (but not hs-CRP), HR 1.09 (1.01-1.19, p=0.036) (deBoer 2012).

Galectin-3 can be expressed in the nucleus, cytoplasm, mitochondrion, cell surface, extracellular space, circulate freely in the blood stream (Brown 2012), and can be measured in blood samples as well as in tumor tissue samples. Normal serum levels range from 5.4-26.2 ng/mL in 95% of the population based on an analysis conducted by the BGM lab on 1099 samples from healthy patients (BG Medicine 2011). Recently, a blood test for galectin-3 has been approved by the FDA for use in assessing prognosis in patients with chronic heart failure (FDA 2012).

The Role of Galectin-3 in Chronic Disease Processes Cancer

Galectin-3 is over-expressed on the surface of cancer cells (Saleh 2009), where it affects tumor growth through several mechanisms. First, galectin-3 acts as a cell surface adhesion molecule that allows cancer cells to aggregate (Tinari 2001). Second, galectin-3 promotes the dissemination of cancer through the circulatory system, representing an important mechanism for cancer metastasis (Wang 2012). Finally, galectin-3 is also involved in angiogenesis (Nangia-Makker 2000, Yu 2007, Wang 2009, Zhao 2009).

Evaluation of galectin-3 is gaining recognition as an assessment tool in oncology, in particular as a diagnostic marker and as a prognostic marker for different cancers (Brown 2012, Chiu 2010). Studies of galectin-3 in oncology to date have focused predominantly but not exclusively on levels of galectin-3 expression in tumor tissue, rather than on circulating galectin-3, which is the basis of the test in heart failure. Tumor expression of galectin-3 may be elevated or suppressed depending on the cancer type and/ or stage; ie., “decreased expression of galectin-3 … detected in breast cancer, colonic cancer, prostate cancer and head and neck cancer compared to that of corresponding normal tissues, [and increased] galectin-3 expression … in pancreatic, vulvar and colonic carcinomas compared to normal tissues” (Brown 2012). More research on the topic is anticipated to be published in the very near future, however, studies of circulating galectin-3 thus far demonstrate an association with increased risk of cancer, and particularly with increased risk of metastasis. The reason for the apparent lack of consistency in effect between tissue expression levels and circulating levels in not known at this time.

As reported above, the PREVEND study found increased all cause mortality associated with circulating galectin-3 (deBoer 2012); for cancer specific mortality, there was a 41% increased risk among the highest quintile, HR 1.41 (1.28-1.56), unadjusted; though this relationship became insignificant after adjustment.

Iurisci et al examined circulating galectin-3 in 99 cancer patients compared with 50 healthy subjects, finding that levels were significantly higher in cancer patients (p=0.014) (2000). Interestingly, when breast cancer patients only (n=35) were compared to normal subjects, there was no significant difference in galectin-3 levels, however, patients with metatstatic breast cancer had significantly higher galectin-3 compared to those with non-metastatic disease (p<0.032) (Iurisci 2000). Similar results were found for patients with gastrointestinal (GI) cancer (n=25), non-samll cell lung cancer (n=26). Among healthy subjects, median levels were 62ng/mL (range 20-313, 95th percentile 184.3 ng/mL), while maximum levels were found among patients with metastatic GI cancers: median 320ng/mL, range 20-950m/L) (Iurisci 2000).

Saussez et al evaluated circulating galectin-3 in 102 patients with head and neck squamous cell carcinomas (HNSCCs) (2008). Galectin-3 levles were significantly higher in cancer patients compared to controls, median 3.2 and 2.39 ng/mL, respectively (p=0.03), and a threshold value of 4.3 ng/mL enabled discrimination between groups at 90% specificity and 36% sensitivity (Saussez 2008). Notably, galectin-3 levels were significantly higher among five patients with metastatic disease compared with the 97 with localized tumors. Further analysis showed a “weak, but nevertheless significant, prognostic value in terms of periods of survival for HNSCC patients” based on being over or under 4.3 ng/mL (Saussez 2008). Finally, levels of galectin-3 were found to decrease in response to treatment (chemo and/ or radiation and/ or surgery) of the primary tumor, compared to pre-treatment (p=0.001).

Other members of the galectin family have been found to be elevated in patients with breast and colorectal cancer (Barrow 2011).

More research is clearly needed to better evaluate the best use of this test in routine practice, however in the meantime galectin-3 holds immense potential as a cancer prognostic marker. In addition, human trials monitoring the effect on galcetin-3 levels in response to cancer treatment are currently lacking (Pieters 2006), however this presents an intriguing area for future research. It is also worth noting that there is little report in the medical literature of any pharmaceutical galectin-3 inhibitors; instead, the primary agent discussed in review articles thus far has been a natural agent, modified citrus pectin (Pieters 2006).

Cardiovascular Disease

As mentioned above, the galectin-3 blood test has recently received FDA approval as a prognostic test for chronic heart failure (2012). Several large studies have shown that elevated levels of plasma galectin-3 are significantly associated with higher risk of death in patients with acute decompensated and chronic heart failure (De Boer 2011a, DeBoer 2011b, Lok 2010, Shah 2010).

In the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study, 1492 patients with ischaemic systolic heart failure were found to differentially respond to statin drugs according to their levels of galectin-3 (Gullestad 2010). Among patients who received rouvastatin, those whose plasma galectin-3 was below the median (≤19.0 ng/mL) had a 1) lower event rate [hazard ratio (HR) 0.65; 95% confidence interval (CI), 0.46-0.92; P= 0.014] and 2) lower total mortality (HR 0.70; 95% CI, 0.50-0.98; P= 0.038) compared with placebo. Notably, there was no benefit from rouvastatin in patients with higher levels of galectin-3.

Another key study was the HF-ACTION study (Felker 2012). In this study, galectin-3 levels were analyzed in 895 patients with chronic heart failure caused by left ventricular systolic dysfunction. Higher galectin-3 levels were associated with measures of heart failure severity, including “higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption” (Felker 2012).

Cardiac fibrosis is gaining significant attention as an important risk factor in cardiac disease, in particular chronic heart failure (CHF) (deFilippi 2010), and galectin-3 plays a central role in mediating fibrosis (Liu 2009). At a site of injury/inflammation, galectin-3 is secreted into the extracellular space, activating resting fibroblasts into matrix-producing fibroblasts, thus promoting fibrosis (Liu 2009). Galectin-3 has also been found to beneficially impact other mechanisms associated with heart failure, including myofibroblast proliferation, inflammation and fibrogenesis, tissue repair, and ventricular and tissue remodeling (Liu 2009).

Other Chronic Disease Preclinical evidence suggests that elevated galectin-3 levels may be linked to an array of other chronic diseases, including autoimmune disease. Levels of circulating galectin-3 have been associated with active disease in patient’s with Behcet’s disease (Ozden 2011), juvenille arthritis (Ezzat 2011), and inflammatory bowel disease (Frolova 2009); while increased local levels have been documented in patients with liver disease (Honsawek 2011, Wanninger 2011) and asthma/ chronic obstructive pulmonary disease (Pilette 2007). Preliminary in vivo studies have found that achieving reductions in circulating galactin-3 levels delivers therapeutic benefit for the diseases in question: arthritis (Forsman 2011, Wang 2010A), inflammatory gastrointestinal conditions (Fowler 2006, Srikanta 2010), hepatic disease (Honsawek 2011, Iacobini 2011), and asthma (Zuberi 2004).

FDA Approved Galectin-3 Serum Assay The direct link between galectin-3 and numerous acute and chronic disease states gives this novel molecule an important role in diagnostics and cardiovascular therapeutics, and this is becoming more widely accepted among the medical community, especially with the advent of a galectin-3 serum assay that can now accurately measure this “active” biomarker.

This inexpensive blood test can also be used by practitioners to assess cancer risk and progression, cirrhosis of the liver, kidney fibrosis, and other inflammation/fibrosis related conditions for which early detection is critical for optimal clinical outcome. Approximately 20% of patients exhibit changes in their galectin-3 levels every three months, and current evidence supports checking glactin-3 levels twice annually in those with stable disease (McCullough 2011). Furthermore, according to McCullough “doubling in galectin-3 level over the course of 6 months, irrespective of baseline value, identifies a high-risk patient in whom additional care … could be warranted” (2011). (See Figure 1 below outlining the reference ranges for normal and elevated serum galectin-3 in relation to disease risk).

Unlike the “bystander” biomarker C-reactive protein (CRP) that only indicates the presence of inflammation, elevated circulating galectin-3 is recognized as an “active” or “culprit” biomarker, since research shows that it actively mediates progression of numerous chronic illnesses. This means that galectin-3 is also a potentially important therapeutic target.

Targeting Galectin-3 with Modified Citrus Pectin

Although there are strong associations between galectin-3 levels and heart failure prognosis, and an impressive body of preclinical research linking galectin-3 levels to a variety of diseases, at present there is a lack of human interventional data on therapies that can lower galectin-3. There is preliminary but promising data coming out of preclinical studies however, with respect to modified citrus pectin for galectin-3 inhibition (Kidd 1996, Nangia-Makker 2002B, Olano-Martin 2003). (See Figure 2 for recommended dosages).

MCP is a form of citrus pectin that has been modified to a specific molecular weight and structure which allows it to be absorbed into the circulation and lends it its specific therapeutic properties. MCP is a complex polysaccharide fiber of repeating galacturonic acid groups with neutral sugar side chains. Regular (unmodified) citrus pectin derived from the pith of citrus fruit has a molecular weight of about 50-300 kiloDaltons, and a degree of esterification over 70%. These characteristics make regular pectin far too large to enter the blood stream. MCP can easily enter the circulation, however, when modified through a specific enzymatic process to achieve a molecular weight of 3-13 kiloDaltons, a degree of esterification under 10%, and its present specific structure (Eliaz 2006, Zhao 2008, Pieters 2006, Kidd 1996). Since galectin-3 is a beta-galactoside binding protein, and MCP is rich in beta-galactose, MCP has the ability to bind galectin-3, blocking galectin-3’s harmful effects (Nangia- Makker 2002A).

MCP is the only natural galectin-3 inhibitor demonstrated in published research that can modify the expression of galectin-3 through the natural galectin-binding affinity of its specific molecular structure, based on these authors’ literature review. For instance, a study in prostate cancer cells found that Gal-3 inhibition by antagonist GCS-100, a modified citrus pectin (MCP) product, increased cisplatin-induced apoptosis of PC3 cells (Wang 2010B). A mouse study found that MCP reduced colon cancer metastases to the liver (Liu 2008). In an animal model of an endothelial cancer, modified citrus pectin (MCP) caused a dose-dependent reduction in cancer cell survival by blocking galectin-3’s anti-apoptotic function (Johnson 2007). Furthermore, MCP sensitized cancer cells to doxorubicin such that the in vitro IC(50) of doxorubicin was reduced by 10.7-fold (Johnson 2007). Another study using breast and colon cancer xenografts models (transplanting cancer cell lines into animals and assessing growth) found that MCP was able to reduce growth, angiogenesis, and metastasis (Nangia- Makker 2002B). Another study found that MCP was able to decrease the adhesion of cancer cells to matrix (Inohara 1994). One study found that MCP can induce activation of NK cells in a leukemia model (Ramachandran 2011). Yan found that MCP has antiproliferative effects in prostate cancer cells (2010). In addition, by inhibiting galectin-3’s anti-apoptotic function and enhancing apoptosis induced by cytotoxic drugs, MCP holds the potential to dramatically increase the efficacy of conventional chemotherapy (Najmeh 2012), as well as natural and botanical compounds. These synergistic effects have been demonstrated in preclinical studies (Johnson 2007, Wang 2010B) and warrant further investigation in human clinical trials.

MCP: Beyond galectin-3

Two uncontrolled studies have examined the effect of MCP in cancer patients (Azemar 2007, Guess 2003). One study found a significantly higher PSA doubling time while on MCP for one year, compared to baseline in seven of 10 subjects (Guess 2003), while Azemar found that MCP increased ratings of quality of life overall after eight weeks (2007). Anti cancer effects were variable, with 11 of 29 assessable patients rated as having stable disease after 8 weeks (2 cycles), while 15 had progressive disease. Side effects included mild GI upset (flatulence, dyspepsia) and pruritis.

MCP has been shown to possess chelating activity in humans. As reported previously in IHP, MCP is a safe and potentially effective chelator of heavy metals and radioactive particles (Gallant 2010). MCP does not deplete essential minerals as other chelation therapies often do, and four uncontrolled trials show that patients reduced their toxic metal load by up to 76% (Eliaz 2006, Zhao 2008). MCP was dosed as 5g three times daily for three to six months.

Conclusion

As this important body of research continues to expand, galectin-3 testing is expected to become an integral component of cardiovascular and other screening panels — as routine as assessing cholesterol levels. There are a number of major laboratories that currently offer galectin-3 testing and with this simple assay, practitioners can gain more accurate insight into the risk, progression and advancement of numerous chronic inflammatory diseases. With the emergence of further research, galectin-3 is poised to become an important marker of cancer prognosis. Conversely, we can observe our patients experiencing significant clinical improvements, through firstline lifestyle modifications as well as through use of agents that can reduce inflammation and expression of galectin-3 – key among them, use of MCP.

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Low Dose Naltrexone

Role as adjunct cancer treatment

Abstract

Research in the area of naltrexone has shown both promise and controversy for cancer treatment. Ongoing validation regarding the differing mechanisms of action, the dosage, and the timing of the dose is required. In reviewing the mechanism of action for low-dose naltrexone, more were identified than originally anticipated, which range from a vague endogenous immune response to a complex mechanisms involving LDN affecting a blockade at the OGF-OGFr axis. This article presents the historical use of naltrexone, the current information about the low-dose options and use recommendations, the receptors involved with some controversial effects on cancer with respect to mechanisms of action, and calls for more evidence in the form of phase three clinical trials.

Naltrexone – Mechanism of Action in Treatment of Cancer

The task of bringing together single dimension information from laboratory research examining cellular, vascular, and endocrine events to understand the three dimensional mechanisms of disease in the human body is daunting. The reliance upon research and scientific principles weighs heavy in cancer where much is unknown about disease progression, especially in the form of metastasis or recurrence. Currently information is elucidated about mechanisms of action, from which arise more questions and theories, which in turn provokes the critically-thinking reader to utilize the available information to the best of their abilities. An example of the evolution of a treatment that was first presented as novel and which is now entering the realm of evidence-based medicine is that of low dose Naltrexone (LDN) for use in autoimmune disease and cancer. For the purpose of this article, LDN and its effects in cancer will be the primary focus.

There is little clinical or research evidence beyond the level of dramatic reports from Dr.’s Bihari, Berkson and Rubin (Berkson 2009) to support the use of LDN in treatment of cancer. The authors present case reports of three people diagnosed with pancreatic cancer, treated successfully with the use of Alpha Lipoic Acid and LDN, and call for clinical trials for further investigation of their protocol. In elucidating the mechanism of action for this success they suggested an endogenous immune response. Suffice to say it is a start, and a proposed mechanism of action may eventually create further research to prove or disprove. Further, there is recent evidence in cell studies elucidating more than one anti-cancer mechanism of LDN. Low-dose Naltrexone (LDN) presents itself with complexity: there are different receptors involved, and the resulting effects of LDN on cancer have varied widely. This article reviews the recent data regarding the mechanisms of action and the proposed resulting effects of LDN in treatment of cancer.

Naltrexone History in Brief Naltrexone is used to treat opioid substance abuse and acts by blocking opioid receptors in the brain. It was approved by the US FDA in 1984 in 50 mg dose increments as a competitive narcotic antagonist, for the purpose of stopping or reducing the effects of a heroin or opium overdose and/or for the reduction of opioid withdrawal symptoms (Lowdosenaltrexone.org May 4 2010). For the purposes of opioid blockade this 50mg ‘high dose’ Naltrexone is in tablet form for oral consumption away from meals. Depending upon the type of addiction there are different prescription regimens ranging from daily to every other day schedules (PubMed Health 2011). There is very little understood about Naltrexone beyond opioid blockade as the patent expiry led to it becoming dormant as a prescription item for a number of years. For the treatment of addiction, ‘high-dose’ Naltrexone exerts opposite effects on the Mu Opioid Protein (MOP) receptor at the plasma membrane, and can inhibit secretion of opioids in both brain and adrenal glands via beta endorphins and enkephalins (Figure 1). Naltrexone has been used to treat opioid overdose, opioid addiction (Gonzalez 2004) and addictions to other substances such as alcohol (Chick 2000, Davidson 1999). Naltrexone is conventionally dosed up to a maximum of 350 mg QD. This high-dose use is limited by the adverse effects which are similar to opioid withdrawal and these effects can even occur in patients without previous exposure to opioids (Hollister 1981).

In contrast the Low-dose naltrexone (LDN) dose ranges from 0.1-4.5 mg QD and has not produced adverse effects. The off-label use of low-dose Naltrexone started with Dr. Bihari and has been in use since the 1980’s, subsequently described via case report as an anti-cancer strategy in 2009 by Berkson and Rubin. LDN has been used off-patent for treatment of autoimmune illnesses and cancer since the late 1980’s. It is compounded into tablets or a powder which is mixed with water for oral consumption. Comparative absorption data and information on suppository or injectable doses is limited and unreliable at this time. LDN interacts with opioid analgesics such as Hydrocodone, Oxycodone, Oxymorphone and other opiate/opioid narcotics and thus should be avoided in such instances. It is recommended to gradually reduce the intake and then eliminate the use of any opioid narcotic for 10-12 days before starting LDN. The compounded powder for oral consumption of LDN has a shorter, temperature-sensitive shelf-life and a bitter taste when taken on its own, in comparison to the compounded LDN tablet for oral consumption (Figure 2) (Fawcett 1997).

Receptor Review

Transmembrane receptors in the human body regulate the majority of cellular metabolism and physiology. The largest group of receptors belongs to a group coupled to G-proteins (G-Protein-Coupled Receptors, or GPCRs) (Lefkowitz 2007). The superfamily of GPCRs regulates metabolism, including cellular replication; they are the targets for drug therapy in treatment of cancer and autoimmune disease (Jacoby 2006, Pierce 2002). The genes encoding μ-, δ-, κ-, ζ- and nociceptin Opioid Proteins (MOP- Figure 1, DOP, KOP, OGFr, NOP respectively) belong in the super-family of the GPCRs (Brown 2008, Corbett 2006, Wang 2001) are the transmembrane receptors targeted in the treatment of narcotic abuse (Wang 2001), and are suggested to be the target in the treatment of autoimmune disease (Zagon 2009) and cancer with LDN (Brown 2008). However, more recent research has indicated that the regulatory effect on cancer cell growth extends beyond that of the MOP and to an endogenous opioid factor also referred to as Met5-Enkephalin or Opioid Growth Factor (OGF, Figure 3), and its receptor the ζ-opioid receptor or Opioid Growth Factor Receptor (OGFr). OGF has a role in growth inhibition and OGFr determines the properties of cell proliferation (Zagon 2003). Ongoing phase one and two trials on squamous cell carcinoma of the head and neck and hepatocellular cancer respectively are investigating how OGF binds and activates the OGFr to inhibit angiogenesis and tumor cell growth (Clinicaltrials.gov 2010A, Clinicaltrials.gov 2010B).

Naltrexone – Past, Present and Future

Naltrexone (Figure 2) was approved by the US FDA in 1984 in 50mg doses (max dose 350mg) and acts as a narcotic antagonist. It is used to treat and stop heroin or opium overdoses and withdrawal (Gonzalez 2004), and to treat substance addiction such as alcoholism (Chick 2000, Davidson 1999). Since the patent expired other uses have thus been investigated. In the 1990’s Dr. Bihari first used LDN to treat people with AIDS and then later on to treat people with cancer (Bihari 1995, Lowdosenaltrexone.

org May 18 2010). There have been reports of successful treatment of various cancers (Berkson 2009, Dagleish 2005, Hytrek 1996, Zagon 2000), AIDS (Bihari 1995, Gekker 2001), Multiple Sclerosis (Cree 2010), Autism (Panskepp 1991), and autoimmune disorders such as Crohn’s Disease (Smith 2007) and fibromyalgia (Brown 2008). Sustained release naltrexone (32mg) has now completed investigation in Phase 2 trials with bupropion for the treatment of obesity (Clinicaltrials.gov 2010B).

Naltrexone – Mechanisms of Action

As an opioid antagonist, high dose (50mg – 350mg) naltrexone blocks secretion of opioids in the brain and adrenal glands via the MOP. At low dose (3-4.5mg) nocturnal dose-timing of naltrexone is hypothesized to block opioid receptor expression (MOP, DOP, KOP) and increases circulation of met-enkephalin (Figure 3) and beta-endorphin for up to six hours. The MOP is hypothesized to play a role in the various responses of the immune system to stress, infection and malignant transformation (Makman 1994). LDN has several proposed theoretical mechanisms of action depending on whether the treatment is targeted for cancer or autoimmune disease. An recent cell study investigation revealed controversy. In the anti-cancer role of LDN the OGF/OGFr axis can be allosterically modulated to create multi-dimensional effects on signaling pathways for cellular replication. Allosteric modulation is also demonstrated by the human immune system and readers will recall that the subtypes of Th cells are allosterically modulated to create immune functionality. According to the investigator Dr. Ian Zagon at Penn State University (e-mail communication May 12, 2010): “All human cancers are equipped with the OGF/OGFr axis and depend on it for regulation of cell proliferation. NTX (naltrexone) works by blocking the OGF-OGFr axis. It causes an up-regulation. If the dose is low enough, you allow time for OGF to interact with OGFr to cause a depression in cell proliferation. If you give repeated low doses or a high dose you get up-regulation but no interaction between peptide and receptor. Since the OGF-OGFr axis is tonically active – it is on all the time and watching over the pace of cell proliferation by inhibitory pathways, blockade of OGF-OGFr by naltrexone continuously allows cells to be unregulated in cell division and you have more cells produced.” For the purpose of illustrating further the complexity of this drug there are several mechanisms of action proposed in treatment of the following different types of cancer:

•In neuroblastoma, the low (3-4.5mg) and high dose (100 mg) naltrexone administered demonstrated a direct modulating effect on oncogenesis. The low dose naltrexone elevated opiate receptors and circulating beta endorphin and met-enkephalin through the four to six hour receptor blockade (McLaughlin 1987) and resulted in decreased oncogenesis.

• A small study of 14 patients with untreatable metastatic solid tumors treated with melatonin (20mg hs) and naltrexone(100mgQD) to augment Interleukin-2 therapy demonstrated that lymphocyte production is amplified compared with melatonin and IL-2 therapy alone (Lissoni 2002).

• In Nude mice with colon cancer (HT-29) treated with 0.1mg/ kg naltrexone demonstrated that tumorigenicity was inhibited by opioids via a 2.5 increase in plasma met5-enkephalin in naltrexone-treated mice and an 85% reduction of binding capacity of 3H-Met5-enkephalin in tumor tissue when compared to the control group (Hytrek 1996).

• In pancreatic cancer MIA PaCa-2 clonal cell lines the singlelow- dose naltrexone-induced amplification of the OGFr axis delayed the G1/S inter-phase of the cell cycle via CDK inhibition of p16 or p21, causing a decrease in CDK4/CDK2 activity and RB protein phosphorylation, thus halting DNA synthesis and subsequent cell growth (Zagon 2007).

It remains to be determined how LDN exerts its effects via either an independent or combined extracellular or cytoplasmic effect on cancer cell replication. These give rise to the confirmation that often LDN is not a single therapy provided in isolation of other cancer treatment, and that there are pharmacokinetic properties to LDN which affect enkephalin production, lymphocyte production, and cyclin dependent kinases on control of the cell cycle.

Summary The number of cancer survivors alive compared to those seeking a cure can be described as an inverse relationship. There is a distinct lack of cancer survivors, in spite of all the enormity of efforts ongoing to seek a cure. Research in the area of naltrexone has shown both promise and controversy for cancer treatment and requires ongoing validation regarding the differing mechanisms of action, the dosage, and the timing of the dose and the type of cancer. In reviewing the mechanism of action for low-dose naltrexone, more were identified than originally elucidated by historical data and case reports. An endogenous immune response has been suggested via case report as one possible theory, as well as an increase in enkephalins, lymphocytes, and allosteric blockade at the OGF-OGFr axis. It is a daily challenge to understand the intended and untoward influences of naltrexone upon tumor cell growth because of the differing receptors involved and to tailor a specific protocol based upon the current evidence for people with cancer. In looking to the future use of LDN, there is a need for collaborative effort between the research bench and the patient that may provide more information regarding the mechanisms of tumor initiation, progression and promotion to help extend the limit of one’s knowledge, skills and judgment when treating the complex disease of cancer.

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