Anything to kill the cancer enemy: from the optimization of chemotherapy, to the improvements in radiotherapy, to the progress of immunological therapies and the discovery of new markers up to the specific metabolism of cancer cells. This last strategy is by no means new: in the 50s and 60s the antitumor therapy began precisely in this way, using analogues of nucleotide bases (6-mercaptopurine, 5-fluorouracil, 2-chloroadenosine, 6-thioguanine among the most famous) to target cell replication at the level of DNA synthesis. Alongside these first molecules, folic acid antagonists (ametopterin, methotrexate) were added, which revolutionized the treatment against leukemia and lymphomas. Drugs based on amino acid antagonists (alanosine, sarcolysin, puromycin) were also tried, but they did not last long as their effects were too generalized and highly disabling. In particular, temporary use had natural antibiotics mimetic of glutamine (azaserin and L-DON). Their principle of use, however, was not wrong as they were designed to counteract the nourishing effects of glutamine on cancer cells.
Doctors and other experts now understand the significant role nutrition plays in health. In fact, it is possible to manage conditions such as diabetes and hypertension through diet alone. However, the role of nutrition in cancer prevention or treatment needs to be explored. In 1999, research was published showing that cultured melanoma cells deprived of amino acids such as phenylalanine and tyrosine died from cell detachment from their substrate (a type of death called anoikis). Twenty years ago, research on the class of enzymes called protein tyrosine kinases (PTKs) was on the crest of the wave, because laboratory studies had unequivocally shown that they were absolutely essential to cell duplication induced by cell growth factors. Protein phosphorylation by PTKs occurs precisely on tyrosine residues; that’s why the researchers thought that by removing tyrosine (and its precursor, phenylalanine) from cell nutrition, it could prevent tumor replication and thus kill cancer cells. And so it was.
The consequence of these studies has been the development of drugs against these proteins, which today are currently used in the treatment of many carcinomas, sarcomas and blood cancers, under the name of “targeted therapy”. Another name with which they are known is the class of drugs “inhibs” (in the DISEASES section of this site, TUMORS group, there are two reviews that speak of this category of drugs).
In a very recent study, mice that ate a diet with reduced levels of a particular amino acid responded better to anticancer treatments. The results are intriguing, but the authors call for caution. The study, published in the journal Nature, examined the role of the amino acid methionine in the treatment of cancer. Methionine is necessary for the functioning of our cells; it is an essential amino acid because our body cannot build it and we have to get it through the food we eat. This amino acid has intrigued researchers for many years. For example, a study published in 1993 found that limiting methionine consumption extended the lifespan of rats. As early as 1987, dietary restriction of phenylalanine and tyrosine in tumor mice had reduced the growth of three different tumor models. In 1998, other experiments on tumor mice treated with 5-fluoruracil and methioninase, an enzyme that destroys this amino acid, had recorded a synergistic effect and partial remission of the tumor mass.
Some researchers have begun to investigate further the potential role of methionine in cancer treatment. Methionine has picked the interest of researchers because it plays an important role in a cellular mechanism that some chemotherapy and radiotherapy drugs target. Scientists know this pathway as mono-carbon metabolism. Additionally, some previous studies have suggested that limiting dietary methionine could have an anticancer effect. Methionine restriction could have broad anticancer properties, targeting a focused area of metabolism, and that these effects would interact with the response to other therapies that also affect the metabolism of mono-carbon units (methyl, methylene, formyl) necessary for DNA synthesis. To investigate, the researchers used a variety of cancer models. First, they tested two types of treatment-resistant cancerous tissue taken from humans and grafted onto mice. When the scientists fed the mice a diet with reduced levels of methionine, tumor growth slowed.
Examining the metabolic details, as expected, they found that methionine restriction reduced tumor growth by hampering mono-carbon metabolism. Next, the scientists used a methionine-restricted diet along with a common low-dose chemotherapy drug just insufficient to shrink the tumor. However, according to the authors, the low-methionine diet combined with the drug led to marked inhibition of tumor growth. When the researchers studied a type of mouse sarcoma that didn’t respond to radiation therapy, they found that a restricted diet with methionine alone wasn’t enough to slow tumor growth. When these mice also received a dose of radiation, tumor growth was significantly slowed. In the next phase of their study, the scientists fed six healthy people a low-methionine diet for 3 weeks. And they found metabolic effects similar to those seen in mouse models.
These data suggest that dietary restriction of methionine induces rapid and specific metabolic profiles in mice and humans, which can be induced in a clinical setting, enhancing the effects of chemotherapies that target these aspects of cancer metabolism. Indeed, mono-carbon metabolism enters into the synthesis of purine bases of DNA (through folic acid), and the chemistry of methyl groups can also affect chromosomal status and gene expression. Methionine actually enters the constitution of SAM, an enzymatic cofactor that transfers methyl groups to proteins and nucleic acids through dedicated enzymes. If used by DNA methyl-transferases, these modify areas of DNA that must be at rest (off); in the case of the protein methyl-transferases (PRMTs and HMTs), the methyl groups go on the proteins attached to the DNA. This allows to regulate other cellular processes, including maturation (differentiation) or cell specialization.
These cellular pathways, among other things, are already the target of current anticancer therapies. One of the medical breakthroughs in the treatment of leukemia, bone marrow tumors and forms of pre-leukemia (myelodysplasia) has been the use of inhibitors of methylation reactions. 5-azacitidine and its homolog decitabine are inhibitors of DNA methyl-transferases, which have been used for twenty years in the management of these conditions with satisfactory results. But they are unlikely to be used as a single agent; rather they go with other low-dose drugs in order to obtain the desired therapeutic response. This indicates that it may be necessary to target more aspects of methionine metabolism for a stable and consistent reduction in tumor mass. However, it is not certain that the deprivation of tyrosine or phenylalanine or methionine can be suitable for any type of tumor. For example, other strategies under investigation involve different aminoacids.
One of the most recent and very recently published research has focused on arginine deprivation in brain cancer (glioblastoma). A joint team of researchers experimented with combined canavanine and arginine deprivation therapy against brain tumors. Under normal conditions, the intracellular homeostasis of arginine depends on food absorption. However, arginine is a semi-essential amino acid as humans can partially synthesize it from the urea cycle. The team noted that after arginine deprivation, proteins extracted from cancer cells had a substantial percentage of canavanine in their place. This non-protein amino acid is contained in certain legumes and is frankly toxic in high dosages. Following this incorrect incorporation into cellular proteins, the morphology of two well-known cultured glioblastoma lines was profoundly altered. The concentration of lamin B1 in the nuclear membrane halved, indicating that the treatment induced the destabilization of the general structure of the nucleus.
As a result of these changes, the cells were no longer able to move away from the original site to metastasize. All these biological events were not reproduced by arginine deprivation alone, but by the simultaneous presence of canavanine. There are currently other strategies aimed at targeting cancer cells by modulating the metabolism of amino acids: Among these, that of interfering with the amino acid serine in prostate cancer and with the amino acid lysine in liver cancer. The overall body of studies could, therefore, help to further establish principles on how dietary interventions can be used to influence cancer outcomes in broader settings.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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