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Tumor necrosis factors are pro-inflammatory cytokines. This means that they are proteins involved in causing inflammation. Two types of these cytokines have been recognized: TNF-alpha and TNF-beta. The names of these proteins are short for tumor necrosis factor, which means tumor necrosis factor. How do tumor necrosis factors work? How are TNF-alpha inhibitors used to treat disease?

Tumor necrosis factorsare responsible for the activation of the process of planned suicide cell death, or apoptosis. It is a mechanism that protects the body against the excessive multiplication of genetically mutated cells. When the apoptosis process fails, carcinogenesis occurs. The pro-apoptotic abilitiesTNF-alphafound clinical application in anti-cancer therapy.

The use of this drug, unfortunately, is associated with serious side effects. TNF-alpha is only rarely administered locally to the tumor area.

TNF inhibitors , which are commonly used in the treatment of autoimmune diseases due to their immunosuppressive and immunomodulatory effects, have a much wider therapeutic potential.

What is apoptosis?

Apoptosis plays an important role in maintaining the balance of the processes of creating and dying cells in the human body. The pathological phenomenon resulting from the inhibition of planned cell death is the formation of neoplasms. One of the mechanisms inducing apoptosis is the activation of receptors located in the cell membrane. These membrane structures are called death domains. Their activation occurs, inter alia, after the attachment of an appropriate signaling molecule, e.g. TNF-alpha.

When apoptosis is initiated due to the stimulation of receptors by the activating substance, the executive phase follows very quickly. Relevant enzymes break down the building blocks of proteins in the cell. The DNA in the nucleus is condensed and then cut into pieces. Eventually, the entire cell fragmented into apopototic bodies which are engulfed by immune feeder cells. The secreted TNF-alpha has the ability to attract neutrophils and stimulate phagocytosis. This is important in removing the cells left over from the cellapoptotic.

Thanks to the process of apoptosis, cellular enzymes do not penetrate and he althy tissues are not damaged during the destruction of the mutated cell.

How do tumor necrosis factors work?

Tumor necrosis factors are produced by cells of the immune system, mainly monocytes and macrophages. The release of TNF is stimulated by such stimuli as:

  • endotoxins
  • cancer cells
  • bacterial toxins
  • parasites
  • viruses
  • some medications

The primary role of TNF is to regulate the activity of immune cells. TNF, which is an endogenous, i.e. a pro-inflammatory substance produced by the body. It has the ability to induce fever, inflammation and inhibit the process of cancer formation. It is also involved in blocking viral replication and generating an immune response in the form of sepsis.

Studies show that deregulation of TNF production is involved in the development of many diseases. This includes Alzheimer's disease, cancer, major depression, psoriasis, and inflammatory bowel disease (IBD).

How does TNF-alpha affect neoplastic changes?

Tumor necrosis factors have a dual nature that is opposite to carcinogenesis. This means that, depending on the dose, they can have anti-cancer properties or stimulate the formation of metastases.

Low levels of TNF stimulate tumor mass growth. Under its influence, the apoptosis of mutant cells is inhibited, while he althy cells surrounding the neoplastic lesion are affected. At the same time, diseased cells adhere to a greater extent to the vascular endothelium. This leads to their wandering through the vessels, which results in the spread of neoplastic changes throughout the body. TNF-alpha levels rise as some cancers develop. The high level of this substance in the blood adversely shows the intensification of disease processes. Therefore, measuring TNF-alpha is used in diagnostics.

High concentrations of TNF-alpha induce hemorrhagic necrosis of solid tumors. This substance causes damage to the endothelium of the tumor's blood vessels. It also inhibits the growth, multiplication and function of cells, both sick and he althy. This fact results, among other things, from the high toxicity of TNF-alpha used as an anti-cancer drug.

Where does the dual mechanism of action of TNF-alpha come from?

These two opposite effects from tumor necrosis factor are due to the dose-dependent response that the substance stimulates death receptors. After their activation, there are two possible pathways for the development of the situation in the cell. One of them is activationprocesses to defend the cell against death. This leads to the synthesis of a wide variety of proteins involved in the survival and multiplication of cells.

The second possible reaction is to start the apoptotic pathway. Thanks to it, the multiplication and differentiation of cancer cells is stopped. However, TNF-induced cell death plays a minor role compared to its overwhelming role in inflammation. The tumor necrosis factor activates the cells of the immune system. It increases the absorption of neutrophils and stimulates the multiplication and specialization of T and B lymphocytes. In this way, it helps to actively remove neoplastic changes.

What are the symptoms of an increase in TNF levels in the body?

Local increase in TNF concentration causes the main symptoms of inflammation:

  • elevated temperature
  • swelling
  • redness
  • pain
  • loss of organ function

Systemic high levels of TNF induce symptoms similar to hypotensive shock. It is a condition in which there is a multi-organ failure and loss of consciousness as a result of the body's acute response to this substance. Therefore, TNF-alpha as an anti-cancer drug is only administered locally within the tumor.

Prolonged exposure to low levels of TNF occurs during the development of neoplastic disease. Such long-term presence of elevated tumor necrosis factor causes wasting syndrome.

Increased levels of TNF-alpha in the body are associated with increased susceptibility to allergies. This substance may also be involved in the development of asthma. Currently, scientists associate the genesis of many autoimmune diseases with abnormal levels of growth factor in the body.

TNF-alpha as a drug

The history of TNF-alpha in medicine began at the end of the 19th century. New York-based surgeon William Coley observed a shrinkage of the malignant tumor after topical administration of streptococci bacteriaStreptococcus pyogenes . In the next stage of the work, the researcher started using microorganisms killed by high temperature. Studies have shown that tumor shrinkage was not related to the live bacteria themselves, but to the substances contained in their cell walls. Haemorrhagic fibrosarcoma necrosis developed in laboratory animals administered polysaccharides, which are part of the bacterial cell walls.

In 1975, a cytokine was isolated that is formed in the immune response to the bacterial polysaccharide discovered by William Coley. It turned out that this is the immune protein, and not bacterial substances, that causes ithemorrhagic necrosis of tumors. The substance was named " tumor necrosis alpha factor " which is TNF-alpha for short.

Alpha tumor necrosis factor has been used as an anti-cancer drug. Due to its strong toxic effect on the body, it cannot be administered systemically. It is only used topically in the treatment of tumors. Research is still being carried out to modify this substance in order to obtain a drug with reduced toxicity and increased effectiveness.

TNF-alpha inhibitors as drugs

TNF inhibitors are drugs that suppress the physiological response to tumor necrosis factor (TNF) as part of the inflammatory response.

The tumor necrosis factor is involved in the development of autoimmune and immune disorders. This group of disorders includes diseases such as:

  • rheumatoid arthritis
  • Ankylosing Spondylitis
  • inflammatory bowel disease
  • psoriasis
  • pyoderma
  • refractory asthma

Therefore, research is still being carried out on new TNF inhibitors that could be used in the treatment of these diseases.

Due to the role of TNF-alpha in the removal of cancer cells, inhibitors of this protein stimulate the formation of neoplastic changes such as lymphomas. Other side effects of these drugs include:

  • infections (especially reactivation of latent tuberculosis)
  • heart failure
  • excitation of autoantibodies
  • injection site reactions

Inhibition of TNF activity can be achieved with monoclonal antibodies. This group of drugs includes:

  • infliximab
  • adalimumab
  • certolizumab
  • golimumab

Blockade of TNF activity can also be induced by using a recombinant receptor protein that blocks the tumor necrosis factor receptor. The drug that works in this way is etanercept.

TNF inhibitors in the treatment of rheumatoid arthritis

Tumor necrosis factor has been shown to play a key role in the development of rheumatoid arthritis. TNF levels have been shown to increase in both the synovial fluid and the synovium of rheumatoid arthritis patients. This leads to the formation of local inflammation.

The clinical use of TNF inhibitors in rheumatoid arthritis has been proven by Marc Feldmann and Ravinder N. Mainia. Anti-TNF drugs help to eliminate the abnormal activity of B cells that are responsible for the development of the disease.

Therapy that combines TNF inhibitors with methotrexate has also been shown to be more effective in restoring quality of life in rheumatoid arthritis sufferers compared to single drug therapy.

TNF inhibitors in the treatment of cancer

Due to the previously described participation of TNF in the formation of metastases, inhibitors of this substance have found application as potential anti-cancer drugs.

Anti-TNF therapy has shown only moderate efficacy in the treatment of cancer.

Infliximab, a TNF-alpha inhibitor, causes prolonged stabilization of the disease in some patients.

Another drug in this group, etanercept, has been studied in the treatment of patients with breast and ovarian cancer. It also showed the stabilization of the disease state in patients.

On the other hand, studies of the use of these drugs in the treatment of patients with advanced pancreatic cancer have not shown a satisfactory efficacy compared to placebo.

Naturally occurring TNF inhibitors

The latest research shows that also active substances contained in plants may have the ability to inhibit TNF-alpha. These are the properties of curcumin found in turmeric and green tea catechins.

There is also research suggesting that the anti-inflammatory properties of cannabis and purple echinacea are associated with the inhibition of tumor necrosis factor.

About the authorSara Janowska, MA in pharmacyPhD student of interdisciplinary doctoral studies in the field of pharmaceutical and biomedical sciences at the Medical University of Lublin and the Institute of Biotechnology in Białystok. A graduate of pharmaceutical studies at the Medical University of Lublin with a specialization in Plant Medicine. She obtained a master's degree defending a thesis in the field of pharmaceutical botany on the antioxidant properties of extracts obtained from twenty species of mosses. Currently, in his research work, he deals with the synthesis of new anti-cancer substances and the study of their properties on cancer cell lines. For two years she worked as a master of pharmacy in an open pharmacy.

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Category:

Oncology