- Email: [email protected]
Chronic metabolic acidosis may be the cause of cachexia: Body fluid pH correction may be an effective therapy
Medical Hypotheses (2008) 70, 1167–1173
http://intl.elsevierhealth.com/journals/mehy
Chronic metabolic acidosis may be the cause of cachexia: Body fluid pH correction may be an effective therapy Gabi Drochioiu
*
Department of Organic Chemistry and Biochemistry, Al. I. Cuza University, 11 Carol I, 700506 Iasi, Romania Received 10 October 2007; accepted 14 November 2007
Summary Cachexia is a pathological state characterized by weight loss and protein mobilization during various diseases. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass. Agents interfering with TNF-a have not been very successful to date. Only eicosapentaenoic acid was able to interfere with the action of proteolysis-inducing factors. An acceleration of proteolysis and branched-chain amino acid oxidation was correlated with chronic metabolic acidosis. Therefore, we suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. Moderate hypoxia might be close related to lactic acid production within the whole body, not only in the cancer cells. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose via muscle proteins, amino acids, alanine, and lactic acid. Our hypothesis is consistent with the most findings reported in literature and opens new ways for cachexia prevention and therapy, such as pH correction or higher oxygenation. c 2007 Elsevier Ltd. All rights reserved.
Introduction Cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass during cancer, infection, the acquired immunodeficiency syndrome, and congestive heart failure [1,2]. Cachectic patients are characterized by weight loss together with anorexia, weakness, anemia and asthenia. At the metabolic level, ca-
* Tel.: +40 722 280328; fax: +40 232201313. E-mail address: [email protected]
chexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores [3]. Hence, most studies on cachexia have concentrated on muscle wasting and its possible impact on complications and survival [3]. Cachexia may be present in the early stages of tumor growth before any signs or symptoms of malignancy. Multiple states of cachexia are associated with underlying inflammatory processes and/or cancer [4]. The mechanisms promoting cachexia are yet to be determined although several theories have been advanced. Reduced food intake does not seem to be the primary cause of cachexia [5].
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.11.007
1168 A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-a, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate [6]. Overexpression of TNF-a in the body is critically involved in many diseases [7]. TNF exerts a variety of effects such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation [8]. TNFa regulates lipolysis in human white adipose tissue. However, agents interfering with TNF-a have not been very successful to date [5]. Only eicosapentaenoic acid (EPA) was able to interfere with the action of proteolysis-inducing factors. Systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) is accompanied by enhanced interleukin 18 (IL-18) expression in skeletal muscle, which may precede muscle weight loss [9]. Glucocorticoids induce muscle protein breakdown and the inhibition of protein synthesis [10]. Among the various mechanisms involved in the pathogenesis of cachexia, cellular hypoxia has long been recognized [11]. Hypoxia is a key parameter that controls tumor angiogenesis and malignant progression [12,13]. Tumor hypoxia can be induced or exacerbated by anemia [14]. Energy state and pHi affect a wide variety of cellular processes, including signal-transduction, contractile protein interaction, and activities of ion pumps and channels [15]. Hypoxia can increase production of lactic acid and thereby promote a decrease in intracellular pH [16–19]. Starting with the observation that the biostructure is partially broken down during hypoxia, it was also suggested that a respiratory and pH imbalance could be involved in the cancer etiology [20]. However, little is known about the relationship between hypoxia, chronic metabolic acidosis, and cachexia. The branched-chain amino acid degradation is accelerated in muscles during cachexia. These amino acids are similarly degraded in vitro in muscles of rats with chronic metabolic acidosis [21]. This work aims at providing an in-depth analysis of current developments concerning biochemical mechanisms of cellular metabolism in the cachectic patients. We suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. The relationship between hypoxia and lactic acid production within the whole body is also discussed. Anorexia is seen as a consequence, but a cause of cachexia.
Drochioiu
Presentation of the hypothesis We propose that the acidosis is a major cause of cachexia (Fig. 1). Chronic metabolic acidosis increases whole body protein turnover, muscle protein degradation, as well as nitrogen excretion, and accelerates amino acid oxidation, which are characteristic to cachexia condition. Thus, moderate decreases in the pH values will result in a higher and non-specific proteolysis of muscle proteins. Long lasting hypoxia might be also close related to lactic acid production within the whole body, not only in the cancer cells. The intensity of lactic fermentation is high in anoxia and hypoxia (Fig. 2), even if the cellular glucose concentration is normal (NGF). Higher glucose concentrations will result in a more intense lactic production, even if the oxygen level is high (HGF). An increase in oxygen partial pressure will stimulate respiratory processes at normal glucose levels (NGR), whereas the respiratory process might be diminished by high glucose levels (HGR). Nevertheless, low glucose level during cachexia is associated with low fat synthesis, and not with high lactate production. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose obtained within the gluconeogenesis process via muscle proteins, amino acids, alanine, and lactic acid. The whole process seems to be a special case of auto-canibalism. Time is an important parameter for cachexia evolution; a slight decrease of pH needs a longer interval to loose the same muscle mass than a lower pH of the body fluids. If we consider blood, pH might decrease from 7.38, which is normal, to 7.33 7.28 in slight acidosis, or even below 7.00 in high acidosis. In the last case, the bodies loose rapidly the fat and the muscular mass. Therefore, we suggest that the main cause of cachexia is the increased acidity in the muscle mass, whereas various concentrations of hormones, proinflammatory cytokines (such as tumor necrosis factor-a, interleukin-6, and leptin) and hypothalamic neuropeptides, glucocorticoids, etc., are close related to cachexia, and not its primary cause. In addition, close relationships between the biochemical and physiological parameters of a given organism such as oxygenation level, hormone concentrations, pH, proteolysis rate, the presence of tumors, the blood pressure, the glucose concentration, etc., are effective in cachexia (Fig. 1). This hypothesis is based on the following: a number of chronic diseases are associated with pronounced loss of fat and muscle mass [1,2];
Chronic metabolic acidosis may be the cause of cachexia High glucose concentration
IFN
Other causes
Anemia
TNF
1169
IL-1
PGs
EPA
Inflammation Glucocorticoids
Low oxygen level
Lack of physical exercises
Hypoxia
Acidosis Poison chemicals
Respiratory diseases
Low blood afflux
Proteins Alanine
Cachexia TNF
Lactic acid
Some drugs
Tumors
Figure 1 Schematic presentation of the role of acidosis in cachexia. According to this hypothesis, acidosis might be a major cause of cachexia, still other factors such as tumor necrosis factor-a (TNF), interleukin-1 (IL-1), IL-6, gammainterferon (IFN), eicosapentaenoic acid (EPA) and prostaglandins, and (PGs) may interfere. Hypoxia generated by high blood glucose concentration, low blood afflux, low oxygen level, etc., could promote acidosis, as well.
Figure 2 Schematic presentation of the relationship between cellular respiratory/fermentative processes and oxygen/glucose levels. The intensity of lactic fermentation is high in anoxia and hypoxia, even if the cellular glucose concentration is normal (NGF). Higher glucose concentrations will result in more intense lactic production, even if the oxygen level is high (HGF). An increase in oxygen partial pressure will stimulate respiratory processes at normal glucose levels (NGR), whereas the respiratory process might he diminished by high glucose levels (HGR).
cachexia may be present in the early stages of tumor growth before any signs or symptoms of malignancy; cachexia is a relatively long lasting process; the ATP-ubiquitin-dependent proteolytic system is responsible for breakdown of myofibrillar proteins and has also been reported to be elevated in starvation, sepsis, and metabolic acidosis; acidosis increases intracellular proteolysis in the muscle cell line; plasma branched-chain amino acid concentrations are lowered by metabolic acidosis; both muscle and other tissues may demonstrate a pHsensitive rate of proteolysis similar to skeletal muscle [21]; and cancer cachexia is not simply a local effect of the tumor. The ubiquitin–proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia [22]. The product of this pathway is oligopeptides
and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. According to our hypothesis, both the ubiquitin–proteasome proteolytic activity and the extralysomal peptidase tripeptidyl-peptidase II one must first increase due to the appearance of abnormal proteins and polypeptides within a non-specific proteolytic process developed at lower pH values. This proteolytic system cannot delete all the proteins, but the unfolding ones. Calculated rates of protein synthesis are statistically higher in acidotic animals, because the essential proteins must be resynthesized. Then, the lack of ATP will result in a progressive decrease in activity for proteasome, whereas the increasing activity of the non-specific proteases determines the formation of smaller peptides and amino acids. The overall
1170 net ATP production is diminished with cancer, which ultimately leads to cancer cachexia [23]. The low serum carnitine levels may also contribute to the development of cachexia in cancer patients [24]. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation [2,25]. On the other hand, the fetus in an expecting mother, does not normally lead to weight loss. According to our hypothesis, these two physiological states are not associated with acidosis characteristic to cachexia. Loss of fat mass has been attributed to increased adipocyte lipolysis rather than a decrease in synthesis [26], and this may be due to tumor factors such as lipid-mobilizing factor (LMF) or TNF-a, both of which can increase cyclic AMP in adipocytes, leading to activation of hormone-sensitive lipase (HSL) [5]. However, low blood glucose concentrations specific to the cachectic patients might be related to a decrease in fat synthesis. Because cachexia differs significantly from starvation, nutritional supplementation must be used in conjunction with other anti-cachexia agents to reverse the chronic systemic inflammatory state and the effects of circulating tumor-derived factors seen in cachexia [27]. Intravenous sodium bicarbonate is commonly used to correct blood pH, as well as dextrose for hypoglycemia. Severe lactic acidosis can be treated by continuous hemodialysis for more than 20 h [28]. In addition, an increase in oxygenation during the physical exercise for cachectic patients could be treatment options although this approach is not effective in all individuals [29].
Evidence for acidity-induced cachexia An acceleration of intracellular muscle proteolysis was found in epitrochlearis muscles from rats with chronic metabolic acidosis [30]. Extracellular acidosis increases intracellular proteolysis in the muscle cell line. On the contrary, alkalosis is associated with a stimulation of protein synthesis and a reduction of protein degradation [31]. The chronic metabolic acidosis not only accelerates the rate of body protein turnover, but also leads to an increase in the net catabolism of protein and nitrogen excretion [21]. The degree of acidosis accompanying chronic renal failure affects the metabolism of branchedchain amino acids (BCAA); it was found a striking direct correlation between the predialysis plasma
Drochioiu bicarbonate concentration and the valine concentrations measured from skeletal muscle biopsies [21]. Plasma BCAA concentrations are lowered by metabolic acidosis despite identical dietary protein intake, suggesting that acidosis stimulates the breakdown of BCAA [30]. A high increase in liver branched-chain ketoacid dehydrogenase (BCKAD) activity is observed in rats with acidosis, whereas kidney BCKAD activity is decreased by acidosis [21]. Plasma leucine, valine, and isoleucine are generally depressed in animals with chronic acidosis compared with control ones receiving an identical intake of all three of the branched-chain amino acids [21]. Children with renal tubular acidosis demonstrate stunted growth, and that the growth rate is improved by eliminating the academia with supplemental sodium bicarbonate [32].
Discussion Cachexia and hypoxia Hypoxia increases the number of pathological mitoses and activates DNA synthesis in rats [33]. Hypoxia/reoxygenation (H/R) may play an important role in regulating Syk activation, and Lck may be involved in this process. H/R differentially regulates Syk phosphorylation and its subsequent interaction and cross-talk with Lck in MCF-7 cells. Moreover, Syk and Lck play differential roles in regulating Sp1 activation and expressions of melanoma cell adhesion molecule (MelCAM), urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF) in response to H/R. Overexpression of wild type Syk inhibited the H/R-induced uPA, MMP-9, and VEGF expression but up-regulated MelCAM expression. MelCAM acts as a tumor suppressor by negatively regulating H/R-induced uPA secretion and MMP-9 activation. The hypoxic ventilatory response (HVR) is triggered by acute hypoxia and precedes a series of other hypoxic cellular responses that include changes in smooth muscle tone and the increased expression of hypoxiainducible proteins such as erythropoietin [34]. Moreover, epoetin alfa can reduce intratumoral hypoxia and, as a result, possibly interrupt one or more hypoxia-driven mechanisms (e.g., HIF-1amediated cell adaptation; VEGF upregulation) [35]. Results revealed striking concordance between patterns of gene expression induced by hypoxia and by a nonspecific 2-OG-dependent
Chronic metabolic acidosis may be the cause of cachexia
1171
dioxygenase inhibitor, dimethyloxalylglycine (DMOG). Many of these responses were suppressed by short interfering RNAs directed against HIF-1a and HIF-2a, with HIF-1a suppression manifesting substantially greater effects than HIF-2a suppression, supporting the importance of HIF pathways. Nevertheless, the definition of genes regulated by both hypoxia and DMOG, but not HIF, distinguished other pathways most likely involving the action of 2-OG-dependent dioxygenases on non-HIF substrates. The concentrations of peroxisome proliferatoractivated receptors (PPAR-a and PPAR-d) are significantly lower in the cachectic chronic obstructive pulmonary disease (COPD) patients than both the noncachetic patients and controls. Disruption of PPAR activity occurs in in vitro conditions of hypoxia [35] and systemic inflammation [1,6], which are common complications of COPD. An increase in oxygenation during cancer treatment correlated with an improved outcome [36]. Hypoxia activates a complex gene expression program mediated by hypoxia-inducible factor 1 (HIF-1a). One of the consequences of HIF-1a activation is up-regulation of glycolysis and hence the production of lactic acid [37].
tissue pH in medullary breast cancers was 6.81, whereas the tissue pH distribution in squamous cell breast cancers was shifted to significantly higher (7.04) values. The increasing tumor weight must not necessarily be accompanied by a continual pH drop [15]. Low tumor pH is, in vivo, generally assumed to be closely interlinked with tissue hypoxia and low blood-flow levels, each of which may individually influence the experimental outcome [45]. The in vivo studies revealed that a particular metabolic micromilieu characterized by hypoxia and even anoxia, a general deprivation of nutrients and an insufficient removal of metabolic waste products, predominantly lactic acid, causing tissue acidosis develops in many malignant tumors due to severe restrictions of convective and diffusive transport [46]. Although acidosis is mainly attributable to excessive production of lactic acid, it also involves carbonic anhydrase IX mediated conversion of CO2 to an extracellular proton and a bicarbonate ion transported to cytoplasm [47]. Carbonic anhydrase IX transcription and activity are induced by hypoxia.
Glycolysis
Many of the same inflammatory factors that promote tumor growth also are responsible for cancer cachexia/anorexia, pain, debilitation, and shortened survival [1]. The inflammatory reactions may arise acutely from traumatic tissue injury or infection, or may be induced chronically by malignant cells, degenerative changes, or by tissue ischemia due to oxygen deficiency [48]. Caspases and cathepsins are involved in apoptosis and inflammation, being enzyme targets for osteoporosis and inflammation, apoptosis-related disorders, and possible targets for cancer, diabetes and obesity [49]. Rheumatoid arthritis is also characterized by increased production of the inflammatory cytokines, tumor necrosis factor-a (TNF-a), IL-1a, IL-1b, and fibroblast growth factor (FGF) 1.
Although tumors commonly exhibit high rates of glycolysis and release lactate, the energy requirement of the tumor does not explain weight loss, because weight loss is common with even small tumors. Cachexia is often found before any signs or symptoms of the cancer [38]. Glucose, lactate, and ATP levels are very heterogeneously distributed in medullary and squamous cell tumors as compared with normal tissue [15]. Almost all tumors release lactate in an amount linearly related to glucose consumption. HIF-1a is essential for the upregulation of enzymes of the glycolytic pathway to supply phagocytes with sufficient levels of ATP [39]. Tumor cells express HIF-1a and upregulate glycolysis through the activation of the energy-sensing enzyme AMP-activated protein kinase (AMPk) [40– 42]. AMP levels rise and activates AMPk [43], which facilitates the ‘‘glycolytic switch’’, and provides a substrate-dependent growth advantage to malignant tumors [44].
Changes in pH The tumoral tissue was found to be acidotic compared with pH values in the normal one. The mean
Inflamation
Conclusions and perspectives A hypothesis was advanced to explain the involvement of acidosis in cachexia, which is consistent with the most findings reported in literature. A variety of predictions can be derived from the hypothesis that cachexia, hypoxia, and low pH of body fluids will often be associated. Increases in the pH of the body fluids will improve the health state
1172 and reduce the weight loss. A biochemical imbalance will be recognized as the main cause of tumor genesis as well as cachexia; the positron emission tomography imaging could demonstrate an increase in hypoxia in tissues before tumor genesis. Cachexia could simply be controlled by eliminating the acidemia with supplemental sodium bicarbonate. However, further research is required to more fully assess the impact of acidosis on survival and cachexia-related disease control in a variety of cancers, AIDS, heart diseases, etc.
Acknowledgment Financial support was by CNCSIS Bucharest (Grant no. 1451/2007).
References [1] MacDonald N. Cancer cachexia and targeting chronic inflammation: A unified approach to cancer treatment and palliative/supportive care. J Support Oncol 2007;5: 157–62. [2] Melstrom LG, Melstrom Jr KA, Ding XZ, Adrian TE. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. Histol Histopathol 2007;22:805–14. [3] Ryde ´n M, Arner P. Fat loss in cachexia—is there a role for adipocyte lipolysis? Clin Nutr 2007;26:1–6. [4] Siddiqui R, Pandya D, Harvey K, Zaloga GP. Nutrition modulation of cachexia/proteolysis. Nutr Clin Pract 2006;21:155–67. [5] Tisdale MJ. Cancer cachexia. Langenbecks Arch Surg 2004;389:299–305. [6] Mak RH, Cheung W. Cachexia in chronic kidney disease: role of inflammation and neuropeptide signaling. Curr Opin Nephrol Hypert 2007;16:27–31. [7] Wan Y, Xue X, Li M, Zhang X, Qin X, Zhang C, et al. Prepared and screened a modified TNF-a molecule as TNF-a autovaccine to treat LPS induced endotoxic shock and TNFa induced cachexia in mouse. Cell Immunol 2007;246: 55–64. [8] Old LJ. Tumor necrosis factor (TNF). Science 1985;230:630–2. [9] Petersen AMW, Penkowa M, Iversen M, Frydelund-Larsen L, Andersen JL, Mortensen J, et al. Elevated levels of IL-18 in plasma and skeletal muscle in chronic obstructive pulmonary disease. Lung 2007:161–71. [10] Menconi M, Fareed M, O’Neal P, Poylin V, Wei W, Hasselgren PO. Role of glucocorticoids in the molecular regulation of muscle wasting. Crit Care Med 2007;35(suppl):S602–8. [11] Mustafa I, Leverve X. Metabolic and nutritional disorders in cardiac cachexia. Nutrition 2001;17:756–60. [12] Chakraborty G, Rangaswami H, Jain S, Kundu GC. Hypoxia regulates cross-talk between Syk and Lck leading to breast cancer progression and angiogenesis. J Biol Chem 2006;281: 11322–31. [13] van Halteren H, Bongaerts G, Kamm Y, et al. Preclinical evidence for a direct link between tumor hypoxia and cancer cachexia. Eur J Cancer 2001;37(suppl 6):S127.
Drochioiu [14] Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. The Oncologist 2004;9(suppl 5):4–9. [15] Leach RM, Sheehan DW, Chacko VP, Sylvester JT. Effects of hypoxia on energy state and pH in resting pulmonary and femoral arterial smooth muscles. Am J Physiol 1998;275(Lung Cell. Mol. Physiol. 19):L1051–60. [16] Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy. The Oncologist 2004;9(suppl 5):31–40. [17] Stu ¨ttgen C, Knu ¨ben G, Po ¨hmann K, Schmidt K, Stuschke M, Thews O, et al. Erythropoietin restores the anemiainduced reduction in radiosensitivity of experimental human tumors in nude mice. Int J Radiat Oncol Biol Phys 2003;55:1358–62. [18] Daneryd P. Epoetin alfa for protection of metabolic and exercise capacity in cancer patients. Semin Oncol 2002;29(suppl 8):69–74. [19] Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. The Oncologist 2004;9(suppl 5):18–30. [20] Drochioiu G. Eugen Macovschi’s concept of biostructure and its current development. In: Savva S, editor. Life and mind. In search of the physical basis. Canada, USA, Ireland & UK: Trafford Publ.; 2006. p. 43–60. [21] May RC, Masud T, Logue B, Bailey J, England B. Chronic metabolic acidosis accelerates whole body proteolysis and oxidation in awake rats. Kidney Int 1992;41:1535–42. [22] Chand A, Wyke SM, Tisdale MJ. Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle. Cancer Lett 2005;218:215–22. [23] Perumal SS, Shanthi P, Sachdanandam P. Energy-modulating vitamins – a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma. Brit J Nutr 2005;93:901–9. [24] Vinci E, Rampello E, Zanoli L, Oreste G, Pistone G, Malaguarnera M. Serum carnitine levels in patients with tumoral cachexia. Eur J Intern Med 2005;16:419–23. [25] Adrian TE. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. Histol Histopathol Cell Molec Biol 2007;22:805–14. [26] Agustsson T, Ryde ´n M, Hoffstedt J, van Harmelen V, Dicker A, Laurencikiene J, et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res 2007;67:5531–7. [27] Couch M, Lai V, Cannon T, Guttridge D, Zanation A, George J, et al. Cancer cachexia syndrome in head and neck cancer patients: part I. Diagnosis, impact on quality of life and survival, and treatment. Head Neck 2007;29:401–11. [28] Guo PYF, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dialysis 2006;19:80–3. [29] Sathyapala SA, Kemp P, Polkey MI. Decreased muscle PPAR concentrations: a mechanism underlying skeletal muscle abnormalities in COPD? Eur Respir J 2007;30:191–3. [30] May RC, Hara Y, Kelly RA, Block KP, Buse MG, Mitch WE. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis. Am J Physiol 1987;252:E712–8. [31] Fuller SJ, Gaitanaki CJ, Sugden PH. Effects of increasing extracellular pH on protein synthesis and protein degradation in the perfused working rat heart. Biochem J 1989;259:173–9. [32] Nash MA, Tourado AD, Greifer I, Spitzer A, Edelman Jr CM. Renal tubular acidosis in infants and children. J Pediatr 1972;80:738–48.
Chronic metabolic acidosis may be the cause of cachexia [33] Vdovenko SV, Timoshin SS. Effect of hypoxia on epithelial cell division in the cornea and tongue of white rats. Biull Eksp Biol Med 1983;96:86–7. [34] Ludwig H, Hudis CA, Goss G, Leyland-Jones B. Epoetin alfa: future directions and future research. Oncologist 2004;9: 70–3. [35] Narravula S, Colgan SP. Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor-a expression during hypoxia. J Immunol 2001;166: 7543–8. [36] Dunst J, Hansgen G, Lautenschlager C, Fu ¨chsel G, Becker A. Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon. Int J Radiat Oncol Biol Phys 1999;43:367–73. [37] Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metast Rev 2007;26:299–310. [38] Tijerina AJ. The biochemical basis of metabolism in cancer cachexia. Dimens Crit Care Nurs 2004;23:37–43. [39] Nathan C. Oxygen and the inflammatory cell. Nature 2003;422:675–6. [40] Shiota G. The hypothesis of Warburg revisited: a metabolic switch in carcinogenesis. Hepatol Res 2006;36:156–7. [41] Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol 2006;18:598–608.
1173
[42] Manka D, Millhorn DE. A potential molecular link between aerobic glycolysis and cancer. Cell Cycle 2006;5:343–4. [43] Hammerman PS, Fox CJ, Thompson CB. Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem Sci 2004;29:586–92. [44] Ashrafian H. Cancer’s sweet tooth: the Janus effect of glucose metabolism in tumorigenesis. Lancet 2006;367: 618–21. [45] Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumor pH to the treatment of malignant disease. Radiother Oncol 1984;2:343–66. [46] Vaupel P, Frinak S, Bicher HI. Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 1981;41:2008–13. [47] Ihnatko R, Kubes M, Takacova M, Sedlakova O, Sedlak J, Pastorek J, et al. Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia. Int J Oncol 2006;29:1025–33. [48] Rittler P, Jauch KW, Hartl W. Metabolische Unterschiede zwischen Anorexie, Katabolie und Kachexie. Akt Erna ¨hr Med 2007;32:93–8. [49] Turk B, Stoka V. Proteasse signaling in cell death: caspases versus cysteine cathepsins. FEBS Lett 2007;581: 2761–7.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
Chronic metabolic acidosis may be the cause of cachexia: Body fluid pH correction may be an effective therapy Gabi Drochioiu
*
Department of Organic Chemistry and Biochemistry, Al. I. Cuza University, 11 Carol I, 700506 Iasi, Romania Received 10 October 2007; accepted 14 November 2007
Summary Cachexia is a pathological state characterized by weight loss and protein mobilization during various diseases. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass. Agents interfering with TNF-a have not been very successful to date. Only eicosapentaenoic acid was able to interfere with the action of proteolysis-inducing factors. An acceleration of proteolysis and branched-chain amino acid oxidation was correlated with chronic metabolic acidosis. Therefore, we suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. Moderate hypoxia might be close related to lactic acid production within the whole body, not only in the cancer cells. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose via muscle proteins, amino acids, alanine, and lactic acid. Our hypothesis is consistent with the most findings reported in literature and opens new ways for cachexia prevention and therapy, such as pH correction or higher oxygenation. c 2007 Elsevier Ltd. All rights reserved.
Introduction Cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass during cancer, infection, the acquired immunodeficiency syndrome, and congestive heart failure [1,2]. Cachectic patients are characterized by weight loss together with anorexia, weakness, anemia and asthenia. At the metabolic level, ca-
* Tel.: +40 722 280328; fax: +40 232201313. E-mail address: [email protected]
chexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores [3]. Hence, most studies on cachexia have concentrated on muscle wasting and its possible impact on complications and survival [3]. Cachexia may be present in the early stages of tumor growth before any signs or symptoms of malignancy. Multiple states of cachexia are associated with underlying inflammatory processes and/or cancer [4]. The mechanisms promoting cachexia are yet to be determined although several theories have been advanced. Reduced food intake does not seem to be the primary cause of cachexia [5].
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.11.007
1168 A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-a, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate [6]. Overexpression of TNF-a in the body is critically involved in many diseases [7]. TNF exerts a variety of effects such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation [8]. TNFa regulates lipolysis in human white adipose tissue. However, agents interfering with TNF-a have not been very successful to date [5]. Only eicosapentaenoic acid (EPA) was able to interfere with the action of proteolysis-inducing factors. Systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) is accompanied by enhanced interleukin 18 (IL-18) expression in skeletal muscle, which may precede muscle weight loss [9]. Glucocorticoids induce muscle protein breakdown and the inhibition of protein synthesis [10]. Among the various mechanisms involved in the pathogenesis of cachexia, cellular hypoxia has long been recognized [11]. Hypoxia is a key parameter that controls tumor angiogenesis and malignant progression [12,13]. Tumor hypoxia can be induced or exacerbated by anemia [14]. Energy state and pHi affect a wide variety of cellular processes, including signal-transduction, contractile protein interaction, and activities of ion pumps and channels [15]. Hypoxia can increase production of lactic acid and thereby promote a decrease in intracellular pH [16–19]. Starting with the observation that the biostructure is partially broken down during hypoxia, it was also suggested that a respiratory and pH imbalance could be involved in the cancer etiology [20]. However, little is known about the relationship between hypoxia, chronic metabolic acidosis, and cachexia. The branched-chain amino acid degradation is accelerated in muscles during cachexia. These amino acids are similarly degraded in vitro in muscles of rats with chronic metabolic acidosis [21]. This work aims at providing an in-depth analysis of current developments concerning biochemical mechanisms of cellular metabolism in the cachectic patients. We suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. The relationship between hypoxia and lactic acid production within the whole body is also discussed. Anorexia is seen as a consequence, but a cause of cachexia.
Drochioiu
Presentation of the hypothesis We propose that the acidosis is a major cause of cachexia (Fig. 1). Chronic metabolic acidosis increases whole body protein turnover, muscle protein degradation, as well as nitrogen excretion, and accelerates amino acid oxidation, which are characteristic to cachexia condition. Thus, moderate decreases in the pH values will result in a higher and non-specific proteolysis of muscle proteins. Long lasting hypoxia might be also close related to lactic acid production within the whole body, not only in the cancer cells. The intensity of lactic fermentation is high in anoxia and hypoxia (Fig. 2), even if the cellular glucose concentration is normal (NGF). Higher glucose concentrations will result in a more intense lactic production, even if the oxygen level is high (HGF). An increase in oxygen partial pressure will stimulate respiratory processes at normal glucose levels (NGR), whereas the respiratory process might be diminished by high glucose levels (HGR). Nevertheless, low glucose level during cachexia is associated with low fat synthesis, and not with high lactate production. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose obtained within the gluconeogenesis process via muscle proteins, amino acids, alanine, and lactic acid. The whole process seems to be a special case of auto-canibalism. Time is an important parameter for cachexia evolution; a slight decrease of pH needs a longer interval to loose the same muscle mass than a lower pH of the body fluids. If we consider blood, pH might decrease from 7.38, which is normal, to 7.33 7.28 in slight acidosis, or even below 7.00 in high acidosis. In the last case, the bodies loose rapidly the fat and the muscular mass. Therefore, we suggest that the main cause of cachexia is the increased acidity in the muscle mass, whereas various concentrations of hormones, proinflammatory cytokines (such as tumor necrosis factor-a, interleukin-6, and leptin) and hypothalamic neuropeptides, glucocorticoids, etc., are close related to cachexia, and not its primary cause. In addition, close relationships between the biochemical and physiological parameters of a given organism such as oxygenation level, hormone concentrations, pH, proteolysis rate, the presence of tumors, the blood pressure, the glucose concentration, etc., are effective in cachexia (Fig. 1). This hypothesis is based on the following: a number of chronic diseases are associated with pronounced loss of fat and muscle mass [1,2];
Chronic metabolic acidosis may be the cause of cachexia High glucose concentration
IFN
Other causes
Anemia
TNF
1169
IL-1
PGs
EPA
Inflammation Glucocorticoids
Low oxygen level
Lack of physical exercises
Hypoxia
Acidosis Poison chemicals
Respiratory diseases
Low blood afflux
Proteins Alanine
Cachexia TNF
Lactic acid
Some drugs
Tumors
Figure 1 Schematic presentation of the role of acidosis in cachexia. According to this hypothesis, acidosis might be a major cause of cachexia, still other factors such as tumor necrosis factor-a (TNF), interleukin-1 (IL-1), IL-6, gammainterferon (IFN), eicosapentaenoic acid (EPA) and prostaglandins, and (PGs) may interfere. Hypoxia generated by high blood glucose concentration, low blood afflux, low oxygen level, etc., could promote acidosis, as well.
Figure 2 Schematic presentation of the relationship between cellular respiratory/fermentative processes and oxygen/glucose levels. The intensity of lactic fermentation is high in anoxia and hypoxia, even if the cellular glucose concentration is normal (NGF). Higher glucose concentrations will result in more intense lactic production, even if the oxygen level is high (HGF). An increase in oxygen partial pressure will stimulate respiratory processes at normal glucose levels (NGR), whereas the respiratory process might he diminished by high glucose levels (HGR).
cachexia may be present in the early stages of tumor growth before any signs or symptoms of malignancy; cachexia is a relatively long lasting process; the ATP-ubiquitin-dependent proteolytic system is responsible for breakdown of myofibrillar proteins and has also been reported to be elevated in starvation, sepsis, and metabolic acidosis; acidosis increases intracellular proteolysis in the muscle cell line; plasma branched-chain amino acid concentrations are lowered by metabolic acidosis; both muscle and other tissues may demonstrate a pHsensitive rate of proteolysis similar to skeletal muscle [21]; and cancer cachexia is not simply a local effect of the tumor. The ubiquitin–proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia [22]. The product of this pathway is oligopeptides
and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. According to our hypothesis, both the ubiquitin–proteasome proteolytic activity and the extralysomal peptidase tripeptidyl-peptidase II one must first increase due to the appearance of abnormal proteins and polypeptides within a non-specific proteolytic process developed at lower pH values. This proteolytic system cannot delete all the proteins, but the unfolding ones. Calculated rates of protein synthesis are statistically higher in acidotic animals, because the essential proteins must be resynthesized. Then, the lack of ATP will result in a progressive decrease in activity for proteasome, whereas the increasing activity of the non-specific proteases determines the formation of smaller peptides and amino acids. The overall
1170 net ATP production is diminished with cancer, which ultimately leads to cancer cachexia [23]. The low serum carnitine levels may also contribute to the development of cachexia in cancer patients [24]. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation [2,25]. On the other hand, the fetus in an expecting mother, does not normally lead to weight loss. According to our hypothesis, these two physiological states are not associated with acidosis characteristic to cachexia. Loss of fat mass has been attributed to increased adipocyte lipolysis rather than a decrease in synthesis [26], and this may be due to tumor factors such as lipid-mobilizing factor (LMF) or TNF-a, both of which can increase cyclic AMP in adipocytes, leading to activation of hormone-sensitive lipase (HSL) [5]. However, low blood glucose concentrations specific to the cachectic patients might be related to a decrease in fat synthesis. Because cachexia differs significantly from starvation, nutritional supplementation must be used in conjunction with other anti-cachexia agents to reverse the chronic systemic inflammatory state and the effects of circulating tumor-derived factors seen in cachexia [27]. Intravenous sodium bicarbonate is commonly used to correct blood pH, as well as dextrose for hypoglycemia. Severe lactic acidosis can be treated by continuous hemodialysis for more than 20 h [28]. In addition, an increase in oxygenation during the physical exercise for cachectic patients could be treatment options although this approach is not effective in all individuals [29].
Evidence for acidity-induced cachexia An acceleration of intracellular muscle proteolysis was found in epitrochlearis muscles from rats with chronic metabolic acidosis [30]. Extracellular acidosis increases intracellular proteolysis in the muscle cell line. On the contrary, alkalosis is associated with a stimulation of protein synthesis and a reduction of protein degradation [31]. The chronic metabolic acidosis not only accelerates the rate of body protein turnover, but also leads to an increase in the net catabolism of protein and nitrogen excretion [21]. The degree of acidosis accompanying chronic renal failure affects the metabolism of branchedchain amino acids (BCAA); it was found a striking direct correlation between the predialysis plasma
Drochioiu bicarbonate concentration and the valine concentrations measured from skeletal muscle biopsies [21]. Plasma BCAA concentrations are lowered by metabolic acidosis despite identical dietary protein intake, suggesting that acidosis stimulates the breakdown of BCAA [30]. A high increase in liver branched-chain ketoacid dehydrogenase (BCKAD) activity is observed in rats with acidosis, whereas kidney BCKAD activity is decreased by acidosis [21]. Plasma leucine, valine, and isoleucine are generally depressed in animals with chronic acidosis compared with control ones receiving an identical intake of all three of the branched-chain amino acids [21]. Children with renal tubular acidosis demonstrate stunted growth, and that the growth rate is improved by eliminating the academia with supplemental sodium bicarbonate [32].
Discussion Cachexia and hypoxia Hypoxia increases the number of pathological mitoses and activates DNA synthesis in rats [33]. Hypoxia/reoxygenation (H/R) may play an important role in regulating Syk activation, and Lck may be involved in this process. H/R differentially regulates Syk phosphorylation and its subsequent interaction and cross-talk with Lck in MCF-7 cells. Moreover, Syk and Lck play differential roles in regulating Sp1 activation and expressions of melanoma cell adhesion molecule (MelCAM), urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF) in response to H/R. Overexpression of wild type Syk inhibited the H/R-induced uPA, MMP-9, and VEGF expression but up-regulated MelCAM expression. MelCAM acts as a tumor suppressor by negatively regulating H/R-induced uPA secretion and MMP-9 activation. The hypoxic ventilatory response (HVR) is triggered by acute hypoxia and precedes a series of other hypoxic cellular responses that include changes in smooth muscle tone and the increased expression of hypoxiainducible proteins such as erythropoietin [34]. Moreover, epoetin alfa can reduce intratumoral hypoxia and, as a result, possibly interrupt one or more hypoxia-driven mechanisms (e.g., HIF-1amediated cell adaptation; VEGF upregulation) [35]. Results revealed striking concordance between patterns of gene expression induced by hypoxia and by a nonspecific 2-OG-dependent
Chronic metabolic acidosis may be the cause of cachexia
1171
dioxygenase inhibitor, dimethyloxalylglycine (DMOG). Many of these responses were suppressed by short interfering RNAs directed against HIF-1a and HIF-2a, with HIF-1a suppression manifesting substantially greater effects than HIF-2a suppression, supporting the importance of HIF pathways. Nevertheless, the definition of genes regulated by both hypoxia and DMOG, but not HIF, distinguished other pathways most likely involving the action of 2-OG-dependent dioxygenases on non-HIF substrates. The concentrations of peroxisome proliferatoractivated receptors (PPAR-a and PPAR-d) are significantly lower in the cachectic chronic obstructive pulmonary disease (COPD) patients than both the noncachetic patients and controls. Disruption of PPAR activity occurs in in vitro conditions of hypoxia [35] and systemic inflammation [1,6], which are common complications of COPD. An increase in oxygenation during cancer treatment correlated with an improved outcome [36]. Hypoxia activates a complex gene expression program mediated by hypoxia-inducible factor 1 (HIF-1a). One of the consequences of HIF-1a activation is up-regulation of glycolysis and hence the production of lactic acid [37].
tissue pH in medullary breast cancers was 6.81, whereas the tissue pH distribution in squamous cell breast cancers was shifted to significantly higher (7.04) values. The increasing tumor weight must not necessarily be accompanied by a continual pH drop [15]. Low tumor pH is, in vivo, generally assumed to be closely interlinked with tissue hypoxia and low blood-flow levels, each of which may individually influence the experimental outcome [45]. The in vivo studies revealed that a particular metabolic micromilieu characterized by hypoxia and even anoxia, a general deprivation of nutrients and an insufficient removal of metabolic waste products, predominantly lactic acid, causing tissue acidosis develops in many malignant tumors due to severe restrictions of convective and diffusive transport [46]. Although acidosis is mainly attributable to excessive production of lactic acid, it also involves carbonic anhydrase IX mediated conversion of CO2 to an extracellular proton and a bicarbonate ion transported to cytoplasm [47]. Carbonic anhydrase IX transcription and activity are induced by hypoxia.
Glycolysis
Many of the same inflammatory factors that promote tumor growth also are responsible for cancer cachexia/anorexia, pain, debilitation, and shortened survival [1]. The inflammatory reactions may arise acutely from traumatic tissue injury or infection, or may be induced chronically by malignant cells, degenerative changes, or by tissue ischemia due to oxygen deficiency [48]. Caspases and cathepsins are involved in apoptosis and inflammation, being enzyme targets for osteoporosis and inflammation, apoptosis-related disorders, and possible targets for cancer, diabetes and obesity [49]. Rheumatoid arthritis is also characterized by increased production of the inflammatory cytokines, tumor necrosis factor-a (TNF-a), IL-1a, IL-1b, and fibroblast growth factor (FGF) 1.
Although tumors commonly exhibit high rates of glycolysis and release lactate, the energy requirement of the tumor does not explain weight loss, because weight loss is common with even small tumors. Cachexia is often found before any signs or symptoms of the cancer [38]. Glucose, lactate, and ATP levels are very heterogeneously distributed in medullary and squamous cell tumors as compared with normal tissue [15]. Almost all tumors release lactate in an amount linearly related to glucose consumption. HIF-1a is essential for the upregulation of enzymes of the glycolytic pathway to supply phagocytes with sufficient levels of ATP [39]. Tumor cells express HIF-1a and upregulate glycolysis through the activation of the energy-sensing enzyme AMP-activated protein kinase (AMPk) [40– 42]. AMP levels rise and activates AMPk [43], which facilitates the ‘‘glycolytic switch’’, and provides a substrate-dependent growth advantage to malignant tumors [44].
Changes in pH The tumoral tissue was found to be acidotic compared with pH values in the normal one. The mean
Inflamation
Conclusions and perspectives A hypothesis was advanced to explain the involvement of acidosis in cachexia, which is consistent with the most findings reported in literature. A variety of predictions can be derived from the hypothesis that cachexia, hypoxia, and low pH of body fluids will often be associated. Increases in the pH of the body fluids will improve the health state
1172 and reduce the weight loss. A biochemical imbalance will be recognized as the main cause of tumor genesis as well as cachexia; the positron emission tomography imaging could demonstrate an increase in hypoxia in tissues before tumor genesis. Cachexia could simply be controlled by eliminating the acidemia with supplemental sodium bicarbonate. However, further research is required to more fully assess the impact of acidosis on survival and cachexia-related disease control in a variety of cancers, AIDS, heart diseases, etc.
Acknowledgment Financial support was by CNCSIS Bucharest (Grant no. 1451/2007).
References [1] MacDonald N. Cancer cachexia and targeting chronic inflammation: A unified approach to cancer treatment and palliative/supportive care. J Support Oncol 2007;5: 157–62. [2] Melstrom LG, Melstrom Jr KA, Ding XZ, Adrian TE. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. Histol Histopathol 2007;22:805–14. [3] Ryde ´n M, Arner P. Fat loss in cachexia—is there a role for adipocyte lipolysis? Clin Nutr 2007;26:1–6. [4] Siddiqui R, Pandya D, Harvey K, Zaloga GP. Nutrition modulation of cachexia/proteolysis. Nutr Clin Pract 2006;21:155–67. [5] Tisdale MJ. Cancer cachexia. Langenbecks Arch Surg 2004;389:299–305. [6] Mak RH, Cheung W. Cachexia in chronic kidney disease: role of inflammation and neuropeptide signaling. Curr Opin Nephrol Hypert 2007;16:27–31. [7] Wan Y, Xue X, Li M, Zhang X, Qin X, Zhang C, et al. Prepared and screened a modified TNF-a molecule as TNF-a autovaccine to treat LPS induced endotoxic shock and TNFa induced cachexia in mouse. Cell Immunol 2007;246: 55–64. [8] Old LJ. Tumor necrosis factor (TNF). Science 1985;230:630–2. [9] Petersen AMW, Penkowa M, Iversen M, Frydelund-Larsen L, Andersen JL, Mortensen J, et al. Elevated levels of IL-18 in plasma and skeletal muscle in chronic obstructive pulmonary disease. Lung 2007:161–71. [10] Menconi M, Fareed M, O’Neal P, Poylin V, Wei W, Hasselgren PO. Role of glucocorticoids in the molecular regulation of muscle wasting. Crit Care Med 2007;35(suppl):S602–8. [11] Mustafa I, Leverve X. Metabolic and nutritional disorders in cardiac cachexia. Nutrition 2001;17:756–60. [12] Chakraborty G, Rangaswami H, Jain S, Kundu GC. Hypoxia regulates cross-talk between Syk and Lck leading to breast cancer progression and angiogenesis. J Biol Chem 2006;281: 11322–31. [13] van Halteren H, Bongaerts G, Kamm Y, et al. Preclinical evidence for a direct link between tumor hypoxia and cancer cachexia. Eur J Cancer 2001;37(suppl 6):S127.
Drochioiu [14] Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. The Oncologist 2004;9(suppl 5):4–9. [15] Leach RM, Sheehan DW, Chacko VP, Sylvester JT. Effects of hypoxia on energy state and pH in resting pulmonary and femoral arterial smooth muscles. Am J Physiol 1998;275(Lung Cell. Mol. Physiol. 19):L1051–60. [16] Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy. The Oncologist 2004;9(suppl 5):31–40. [17] Stu ¨ttgen C, Knu ¨ben G, Po ¨hmann K, Schmidt K, Stuschke M, Thews O, et al. Erythropoietin restores the anemiainduced reduction in radiosensitivity of experimental human tumors in nude mice. Int J Radiat Oncol Biol Phys 2003;55:1358–62. [18] Daneryd P. Epoetin alfa for protection of metabolic and exercise capacity in cancer patients. Semin Oncol 2002;29(suppl 8):69–74. [19] Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. The Oncologist 2004;9(suppl 5):18–30. [20] Drochioiu G. Eugen Macovschi’s concept of biostructure and its current development. In: Savva S, editor. Life and mind. In search of the physical basis. Canada, USA, Ireland & UK: Trafford Publ.; 2006. p. 43–60. [21] May RC, Masud T, Logue B, Bailey J, England B. Chronic metabolic acidosis accelerates whole body proteolysis and oxidation in awake rats. Kidney Int 1992;41:1535–42. [22] Chand A, Wyke SM, Tisdale MJ. Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle. Cancer Lett 2005;218:215–22. [23] Perumal SS, Shanthi P, Sachdanandam P. Energy-modulating vitamins – a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma. Brit J Nutr 2005;93:901–9. [24] Vinci E, Rampello E, Zanoli L, Oreste G, Pistone G, Malaguarnera M. Serum carnitine levels in patients with tumoral cachexia. Eur J Intern Med 2005;16:419–23. [25] Adrian TE. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. Histol Histopathol Cell Molec Biol 2007;22:805–14. [26] Agustsson T, Ryde ´n M, Hoffstedt J, van Harmelen V, Dicker A, Laurencikiene J, et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res 2007;67:5531–7. [27] Couch M, Lai V, Cannon T, Guttridge D, Zanation A, George J, et al. Cancer cachexia syndrome in head and neck cancer patients: part I. Diagnosis, impact on quality of life and survival, and treatment. Head Neck 2007;29:401–11. [28] Guo PYF, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dialysis 2006;19:80–3. [29] Sathyapala SA, Kemp P, Polkey MI. Decreased muscle PPAR concentrations: a mechanism underlying skeletal muscle abnormalities in COPD? Eur Respir J 2007;30:191–3. [30] May RC, Hara Y, Kelly RA, Block KP, Buse MG, Mitch WE. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis. Am J Physiol 1987;252:E712–8. [31] Fuller SJ, Gaitanaki CJ, Sugden PH. Effects of increasing extracellular pH on protein synthesis and protein degradation in the perfused working rat heart. Biochem J 1989;259:173–9. [32] Nash MA, Tourado AD, Greifer I, Spitzer A, Edelman Jr CM. Renal tubular acidosis in infants and children. J Pediatr 1972;80:738–48.
Chronic metabolic acidosis may be the cause of cachexia [33] Vdovenko SV, Timoshin SS. Effect of hypoxia on epithelial cell division in the cornea and tongue of white rats. Biull Eksp Biol Med 1983;96:86–7. [34] Ludwig H, Hudis CA, Goss G, Leyland-Jones B. Epoetin alfa: future directions and future research. Oncologist 2004;9: 70–3. [35] Narravula S, Colgan SP. Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor-a expression during hypoxia. J Immunol 2001;166: 7543–8. [36] Dunst J, Hansgen G, Lautenschlager C, Fu ¨chsel G, Becker A. Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon. Int J Radiat Oncol Biol Phys 1999;43:367–73. [37] Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metast Rev 2007;26:299–310. [38] Tijerina AJ. The biochemical basis of metabolism in cancer cachexia. Dimens Crit Care Nurs 2004;23:37–43. [39] Nathan C. Oxygen and the inflammatory cell. Nature 2003;422:675–6. [40] Shiota G. The hypothesis of Warburg revisited: a metabolic switch in carcinogenesis. Hepatol Res 2006;36:156–7. [41] Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol 2006;18:598–608.
1173
[42] Manka D, Millhorn DE. A potential molecular link between aerobic glycolysis and cancer. Cell Cycle 2006;5:343–4. [43] Hammerman PS, Fox CJ, Thompson CB. Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem Sci 2004;29:586–92. [44] Ashrafian H. Cancer’s sweet tooth: the Janus effect of glucose metabolism in tumorigenesis. Lancet 2006;367: 618–21. [45] Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumor pH to the treatment of malignant disease. Radiother Oncol 1984;2:343–66. [46] Vaupel P, Frinak S, Bicher HI. Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 1981;41:2008–13. [47] Ihnatko R, Kubes M, Takacova M, Sedlakova O, Sedlak J, Pastorek J, et al. Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia. Int J Oncol 2006;29:1025–33. [48] Rittler P, Jauch KW, Hartl W. Metabolische Unterschiede zwischen Anorexie, Katabolie und Kachexie. Akt Erna ¨hr Med 2007;32:93–8. [49] Turk B, Stoka V. Proteasse signaling in cell death: caspases versus cysteine cathepsins. FEBS Lett 2007;581: 2761–7.
Available online at www.sciencedirect.com