Cancer is a terrible disease that is lethal in many cases. Therefore several new avenues are being pursued to figure out an ideal treatment. Arginine is an amino acid that has been found to have a role in cancer treatment.
TRANSPORT OF ARGININE:
Arginine is an amino acid that enters into cells via special receptors and transporter. Once inside the cell which may be a cancer cell, Arginine produced nitric oxide (NO). NO produced by Arginine has different roles in tumor production and progression, which we will discuss soon.
Arginine transport is affected by several things. Tumor Necrosis Factor (TNF) and cytokines, both of which are produced by tumors as well as inflammation, help this transport and the production of NO.
On the other hand, if Arginine is metabolized by its enzyme, arginase, then less Arginine will be present for conversion into NO.
AFFECT OF ARGININE METABOLISM ON TUMOR CELLS:
There are certain tumor cells that need Arginine to survive. Human cells can normally make their own Arginine via an enzyme known as arginosuccinase synthase (AS). However, tumor cells do not have this enzyme and hence cannot formulate Arginine. Therefore, studies are being conducted to limit the level of Arginine in cancer cells.
One such study, an enzyme called Arginine deaminase was delivered to patients with liver cancer. This broke down Arginine in cancer cells. This enzyme had to be given in high doses and frequent intervals as it breaks down quickly once inside cells. However, the results were favorable with 2 patients out of 19 recovering completely.
HOW DOES CANCER DEVELOP?
During chronic inflammation, NO is produced. This may lead to the formation of cancer cells. For example, in ulcerative colitis, which is a disease of choric inflammation of the intestines, NO is produced. Patients with ulcerative colitis may develop colon cancer and this has been postulated to be because of long term exposure of cells to NO.
Other cancers that have been suggested to be caused or influenced by NO are cholangiocarcinoma (of gall bladder), lung cancer, metastatic breast cancer and stomach cancer in patients with longstanding ulcers. This may occur because NO promotes new blood vessels for the growth of tumors and prevent the apoptosis of tumor cells. NO also acts on cell DNA, damaging it and preventing its repair. As a result it helps in the initiation of cancer.
PROGRESSION OF CANCER:
NO has three forms known as iNOS, eNOS and nNOS. All three of them have been found to be present in tumor cells and help cells that are already cancerous to progress. They help these cells in dividing and invading other tissues. Metalloproteinase helps tumor cells in invasion and NO increases their expression. These claims are further supported by the finding that inflammatory mediators in breast cancer cells help transport both Arginine and NO into tumor cells, thus helping the cells divide and spread.
ROLE OF NO IN CELL DEATH:
NO activates and mediates the process of cell death, known as apoptosis. Depending on the levels of NO, this may occur even in some tumor cells. NO mediates cell death during inflammation, when cytokines cause the production of NO. However, there are certain cells like liver cells that do not respond to NO by dying.
As a rule of thumb, high levels of NO kills cells while lower levels can prevent cells from dying. Therefore, NO can both induce and prevent apoptosis, depending on its levels and the type of cell.
NEW BLOOD VESSEL FORMATION:
Tumor cells need high blood levels to survive and hence they produce new blood vessels. Although NO affects this process, the way it affects is not entirely understood. Research shows that NO may either support or stop new vessel formation, depending on its levels. Generally though NO promotes blood vessel formation by enhancing factors that regulate this process. It has therefore been postulated that controlling NO induced vessel formation may be a new avenue of cancer cure that needs to be further evaluated.
ROLE OF NO IN IMMUNE SYSTEM:
NO causes toxicity in macrophages which are cells that destroy germs and cancer cells. This was described by Hibbs and his colleagues. This cytotoxicity due to NO has been shown to occur in other immune cells too like T-cells. This loss of immune cells helps cancer cells to spread unchecked. When tumor cells produce NO, this results in suppression of the natural immune system and hence tumor progression.
NO also helps tumor cells in binding to platelets which prevents these cells from being killed by immune cells; allowing them to spread to distant sites.
SO HOW CAN ARGININE AND NO BE MANIPULATED TO FIGHT CANCER?
Understanding all these processes provide us with various new solutions to cancer. Controlling the levels of Arginine induced NO can provide novel therapy approaches. NO is also useful as it increases radiation effects. As mentioned, high levels of NO can also cause apoptosis.
As is evident from this whole discussion, the role of NO is far from completely understood. While it augments cancer in several cases, in also affects the functioning of chemo agents like Adriamycin and has a beneficial result when NO is given before chemotherapy. Therefore, the effects of NO need to be further studied and evaluated as this is an avenue worth exploring.