Methotrexate was one of the first approved anticancer drugs, and is a cornerstone of modern chemotherapy for the treatment of certain solid tumours and blood cancers. However, this therapy must often be stopped prematurely because of its high toxicity in patients\u2019 healthy cells.\u00a0Writing in\u00a0Nature<\/i><\/a>, Kanarek\u00a0et al.<\/i>1<\/a><\/sup>\u00a0report that degradation of the amino acid histidine can increase the sensitivity of cancer cells to methotrexate, and the results suggest that this approach can also help to lower the side effects of methotrexate treatment in mouse models.<\/p>\n An enzyme cofactor termed folate is required for DNA and protein synthesis. In 1948, it was found2<\/a><\/sup>\u00a0that leukaemia is particularly sensitive to drugs that block folate synthesis. Methotrexate inhibits the enzyme dihydrofolate reductase (DHFR), which synthesizes the active form of folate known as tetrahydrofolate (THF) from its precursor dihydrofolate (DHF) (Fig. 1). However, when this drug is used in the clinic, it can substantially reduce the level of folate in healthy cells \u2014 a side effect that is only partially relieved by taking folate supplements. If this toxicity reaches a level that compromises the function of healthy cells, therapy may have to be stopped prematurely. There is therefore great interest in trying to reduce the side effects of methotrexate treatment.<\/p>\n <\/p>\n Figure 1 | The effectiveness of the cancer drug methotrexate can be improved by histidine degradation.\u2002a<\/b>, The cofactor tetrahydrofolate (THF) is required for the function of enzymes, including those that catalyse processes needed for cell proliferation. The enzyme dihydrofolate reductase (DHFR) generates THF from dihydrofolate (DHF), and this catalytic reaction can be inhibited by the anticancer drug methotrexate. Kanarek\u00a0et al.<\/i>1<\/a><\/sup>\u00a0report that, in mouse models and human cell lines, the sensitivity of cancer cells to methotrexate can be boosted by the metabolic degradation of the amino acid histidine. Histidine is metabolized to the amino acid glutamate through a series of intermediate molecules (black circles) in a pathway that requires the enzyme histidine ammonia lyase (HAL), and, crucially for this effect on methotrexate treatment, the THF-dependent enzyme formimidoyltransferase cyclodeaminase (FTCD).b<\/b>, In cancer cells, a large pool of THF is available for THF-dependent enzymes, such as FTCD or those needed for cell proliferation.\u00a0c<\/b>, In methotrexate-treated cancer cells, a decrease in THF levels reduces the activity of these enzymes and thereby reduces tumour growth.\u00a0d<\/b>, The authors report that tumour growth in mice given methotrexate and a histidine-rich diet was substantially decreased compared with\u00a0c<\/b>. This might be because histidine degradation co-opts THF for use with FTCD, thereby enhancing the effect of methotrexate.<\/span><\/p>\n<\/figcaption><\/figure>\n <\/p>\n <\/p>\n To investigate the processes that affect the cellular response to methotrexate, Kanarek\u00a0et al.<\/i>\u00a0used a cell line derived from a person with leukaemia. They employed a gene-editing technique that prevents the expression of individual genes throughout the entire genome in such cells, and tested whether a decrease in the expression of any particular gene reduced the cells\u2019 sensitivity to methotrexate. One such gene that they identified encodes a protein called SLC19A1, which transports folate and methotrexate into cells. This result was unsurprising, given that SLC19A1 has previously been linked3<\/a><\/sup>\u00a0to sensitivity to methotrexate, but it confirmed the power of the authors\u2019 approach.<\/p>\n Kanarek and colleagues found that decreasing the expression of a gene that encodes the enzyme formimidoyltransferase cyclodeaminase (FTCD) also reduced the sensitivity of the cancer cells to methotrexate. FTCD degrades histidine, an amino acid that humans must obtain from their diet because the body cannot synthesize it. The authors reasoned that, because FTCD requires THF as a cofactor for its activity, a decrease in the intracellular levels of FTCD could help to limit the reduction of cellular pools of THF that occurs with methotrexate treatment. Consistent with this hypothesis, the authors found that when the levels of FTCD were reduced by gene editing, THF depletion in human cancer cells treated with methotrexate was less than that seen in methotrexate-treated cells in which FTCD levels were not reduced.<\/p>\n <\/p>\n![\"\"](\"https:\/\/media.nature.com\/w800\/magazine-assets\/d41586-018-05573-4\/d41586-018-05573-4_15910330.jpg\")
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