Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (v.10, #4)

Role of Inflammation in the Evolution of Cancer DiseaseIn the course of its evolution cancer induces in the host changes of the immune system and energy metabolism which deeplyaffect its clinical conditions so much so that in some cases they are responsible for the death [1]. Several symptoms areassociated to these events and involve various organs and systems: anorexia, nausea, weight loss (with reduction of lean massand adipose tissue), enhanced increase of energy metabolism (with changes of the glucidic, lipidic and protein metabolism),immunodepression, anemia, fatigue.It is difficult to establish the exact moment when such changes actually start, but it could be hypothesized that they are theconsequence of the interactions between the tumor and the host [2].The hypothesis that the presence of the tumor and its continuous growth are responsible for the increased energy expenditureand for the progressive weight loss has been considered the most reliable so far. The presence in the host of continuouslygrowing neoplastic tissue justifies by itself the increased energy needs; moreover, it is accompanied by the energy expenditureassociated with chronic activation of the immune system, trying to counteract the tumour, which is energetically very costly [3].However, the energy metabolism in cancer patients is affected by the onset, during the disease evolution, of symptoms such asanorexia, nausea and vomiting, which prevent a normal nutrition and thus a regular supply of glucose, lipids, proteins andvitamins [4]. The same molecules (cytokines) which regulate both the tumor development and the immune system functions areresponsible for these symptoms [5, 6]. Thus in advanced cancer patients, tumor growth and immune system activationdetermine an overall metabolic picture characterized by: - Increased glucidic, lipid and protein requirements;- Difficulty to introduce these substances with food because of anorexia, nausea and vomiting;- Resorting to glucogenesis with depletion of protein and lipid stores and thus loss of weight;- Difficult use of new formed glucose because of hypoinsulinemia and/or peripheral resistance to insulin;- Oxidative damage induced by ROS on DNA, membrane lipoprotein, and enzymes and coenzymes which play a majorrole in the regulation of the main cell catabolic pathways [7]......

In the course of its evolution the neoplastic disease is characterized by changes of the immune system andenergy metabolism which deeply affect patient clinical conditions so much so that in some cases they are responsible forpatient's death. Several symptoms are associated to these events and involve various organs and systems: anorexia,nausea, weight loss (with reduction of lean mass and adipose tissue), enhanced increase of energy metabolism withchanges of the glucidic, lipidic and protein metabolism, fatigue, immunodepression, anemia. It is difficult to establish theprecise moment when such changes actually start, but it could be hypothesized that they are the consequence of theinteractions between the tumor and the host. The hypothesis that the presence of the tumor and its continuous growth areresponsible for the increased energy expenditure and for the progressive weight loss, has been considered the mostreliable so far. The presence in the host of continuously growing neoplastic tissue justifies by itself the increased patientenergy needs; it is however accompanied by energy expenditure associated with chronic activation of the immune system,trying to counteract the tumour. The metabolic scenario is thus of two systems that require a continuous supply of energysubstrates, particularly glucose. Glucose oxidation is the main energy source produced as ATP. A further glucose amountis also involved for the synthesis, through the phosphate pentose pathway, of compounds with high reducing poweressential for the neutralisation of reactive oxygen species (ROS) produced during the various steps of the energymetabolism. The energy metabolism in cancer patients is affected by the onset, during the disease evolution, of symptomssuch as anorexia, nausea and vomiting, which prevent a normal nutrition and thus a regular supply of glucose, lipids,proteins and vitamins. Antiblastic treatments and the same molecules (cytokines) which regulate the devolpment of thetumor and the immune system functions are responsible for these symptoms. Thus the finding that patients with solidtumors in advanced stages show a severe disruption of immunologic functions characterized by cell mediated immunitydeficit and elevated serum levels of macrophage cytokines and acute phase proteins is of particular interest. High serumconcentrations of cytokines and inflammatory proteins are associated with high levels of ROS and low levels ofantioxidant enzymes. Tumor growth and immune system activation thus determine an overall metabolic picturecharacterized by: -increased glucose, lipid and protein requirements;-difficulty to introduce these substances with foodbecause of anorexia, nausea and vomiting;-resorting to glucogenesis with depletion of protein and lipid stores and thusloss of weight;-difficult use of new formed glucose because of hypoinsulinemia and/or peripheral resistance to insulin;-oxidative damage induced by ROS on DNA, membrane lipoprotein, and enzymes and coenzymes which play a major rolein the regulation of the main cell catabolic pathways. These mechanisms are involved in the development of the mainsymptoms of advanced cancer patients, i.e. weight loss, anemia and fatigue. According to this rationale a therapeuticapproach aimed to target the inflammatory and metabolic pathways altered in the advanced neoplastic disease should bedeveloped to impact patient symptoms and quality of life.

The Immune System of Cancer Patients by Carolina Torronteguy, Ana Paula Souza e Cristina Bonorino (262-274).
Although a great body of evidence is available on the immunosuppressive strategies employed by tumors inorder to grow, cancer patients are not considered immunosuppressed individuals. Chemotherapy used in different cancertreatments frequently leads to leucopenia and affects immune responses. Tumors of the immune system can also causeimmune alterations, due to their very nature. However, in the absence of preventive routine exams, patients can beartumors for rather long periods of time without any specific indication, not being particularly prone to contractinginfectious diseases compared to cancer free individuals. In this review, we analyze the existing data on the effects oftumors on the immune system of cancer patients. An interesting pattern emerges, suggesting that immunosuppressionexerted by tumors is mainly local, rather than systemic. However, some alterations in DCs of cancer patients have beenrecently described, indicating the interactions between tumor and immune cells may be more complex than previouslyimagined. This has important implications of the design of anti-tumor therapies as well as in patient quality of life.

Pro-Inflammatory Cytokines and their Actions on the Metabolic Disturbances Associated with Cancer: Implications in Cachexia by Josep M. Argiles, Miriam Toledo, Francisco J. Lopez-Soriano, Silvia Busquets (275-280).
The main aim of the present review is to summarize and evaluate the different molecular mechanisms andcatabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promisingclinical investigations.

Metabolic Changes in Cancer Patients by Clelia Madeddu, Antonio Maccio, Giovanni Mantovani (281-285).
In advanced cancer patients, energy metabolism is severely compromised by the occurrence, during the diseaseprogression, of symptoms such as anorexia, nausea and vomiting, which do not allow for a normal nutrition and so aregular supply of carbohydrates, proteins, amino acids and vitamins. In addition to the reduced food intake, importantchanges of energy metabolism and biochemical/metabolic abnormalities in carbohydrate, protein and lipid biochemistryand metabolism have been observed. The most important carbohydrate abnormalities observed in cachectic cancerpatients are increased glucose synthesis, gluconeogenesis and Cory cycle activity, insulin resistance, and decreasedglucose tolerance. Protein metabolism changes seem to depend mainly from the lack of body adjustment to the increasedenergy demands and the inadequate food intake, which determines the activation of glucogenesis starting in particularfrom protein substrates. From a clinical point of view this metabolic condition is characterized by skeletal muscle atrophyand hypoalbuminemia. Moreover, hypertrigliceridemia, increase of free fatty acids, depletion of fat stores and decrease ofLPL concentrations and activity, which is closely related with weight loss, have been constantly observed in advancedcancer patients. It has been suggested that the chronic action of mediators released by tumour cells and immune cellscounteracting tumour is the main cause of the metabolic abnormalities characterising the cachectic neoplastic patient. Inparticular, proinflammatory cytokines IL-1, TNF-α and IL-6 play a central role in the pathogenesis of metabolicderangements associated with cancer-related cachexia. It may be hypothesised that, during the initial phases of neoplasticdisease, the synthesis of proinflammatory cytokines leads to an efficient antineoplastic effect. However, their chronicactivity leads to severe alterations of cell metabolism, with deleterious effects on body composition, nutritional status andimmune system efficiency.

Oxidative Stress and its Clinical Consequences: Relationship between Diabetes and Cancer by Victor M. Victor, Antonio Hernandez-Mijares, Milagros Rocha (286-298).
Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditionscharacterises the development of oxidative stress and diseases including cancer and diabetes. These ROS are releasedprincipally from mitochondria but also from other sources. Oxidative stress seems to play an important role inmitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS aregenerally necessary for the proper functioning of the cell, but excessive ROS production can be harmful, and soantioxidant defenses are required. Diabetes and cancer are heterogeneous, multifactorial, severe and chronic diseases.Epidemiological studies clearly indicate that the risk of several types of cancer (including that of the breast, colorectum,female reproductive organs, liver, pancreas and urinary tract) is higher in diabetic patients. Hyperinsulinemia appears topromote cancer in diabetic patients, as insulin is a growth factor with metabolic and mitogenic effects and its action inmalignant cells is favoured by mechanisms that act at both receptor and post-receptor levels. Obesity, hyperglycemia andincreased oxidative stress may also contribute to an increased risk of cancer in diabetes patients. In conclusion, diabetesand cancer are conditions related with oxidative stress; a complex relationship that requires clinical attention.

Inflammation and Anemia by Mya Thein, William B. Ershler (299-314).
Anemia is a common cause of morbidity in the general population as it contributes to diminished quality of lifeand reduced physical and cognitive function. Inflammation is a major factor in the pathogenesis of anemia and thus,anemia is commonly observed in patients with acute and chronic infection, and other inflammatory conditions includingcancer, arthritis, atherosclerosis, and diabetes. The mechanisms whereby inflammation may result in anemia are complexand incompletely understood although the recent discovery of the importance of a hepcidin production by the liver inresponse to inflammatory (among other) signals has improved our understanding as this cytokine is an important regulatorof iron trafficking and utilization. Thus, although the anemia of inflammation remains difficult to reverse, optimism ishigh that we will soon have therapies directed at the mediators of anemia and these hold the promise of affording a majortherapeutic advance.

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especiallycancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cancer-relatedanorexia/cachexia syndrome (CACS) is a complex challenge that should address the different causes underlying thisclinical event with an integrated or multimodal treatment approach targeting the different factors involved in itspathophysiology. Among the treatments proposed in the literature for CACS, some proved to be ineffective, namely,cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currentlyconsidered the best available treatment option for cancer-related cachexia, and they are the only drugs approved inEurope. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far includeeicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-α MoAb. Several emerging drugs have shown promisingresults but are still under clinical investigation (thalidomide, selective cyclooxygenase-2 (COX-2) inhibitors, ghrelinmimetics, insulin, oxandrolone, and olanzapine). However, to date, despite several years of co-ordinated efforts in basicand clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking,mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that onesingle therapy may not be completely successful in the treatment of cachexia. A more effective approach might be acombination therapy targeting the different mechanisms contributing to CACS.