Resistance to antifolates and adverse side effects highlight the growing need for novel strategies to target 1C metabolism. Furthermore, antifolates, which broadly inhibit folate-mediate reactions, can manifest a series of side effects in normal proliferating tissue, such as damage to the gastrointestinal epithelium and impaired haematopoiesis. For instance, AML blasts have a decreased ability to retain substantial MTX levels intracellularly. As further discussed below, limited application of MTX is linked to resistance mechanisms that cancer cells acquire to minimise the effectiveness of antifolates. Interestingly, MTX is routinely used only in the treatment of ALL and central nervous system (CNS) lymphoma, even though all blood cancer cell lines demonstrate high sensitivity. These data suggest that targeting 1C metabolism might be an appealing option for the treatment of various blood cancers. Analysis of publicly available data on the sensitivity of almost 700 cancer cell lines to MTX demonstrates that haematological cancer cell lines show high sensitivity to this antifolate, with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) cell lines displaying the highest sensitivity (Fig. Since then, methotrexate (MTX), likely the most well-known antifolate, has been used to treat a variety of neoplastic and inflammatory diseases. With regards to the association of the folate metabolism to blood cancers, the idea that antagonists of folates could reduce the proliferation of malignant cells in paediatric leukaemia gave rise to modern cancer therapy and a class of drugs known as antifolates. As animals cannot synthesise folate, insufficient dietary intake can cause neural tube defects in developing foetuses and anaemia. įolate metabolism, considered the core of a broader set of transformations known as one-carbon (1C) metabolism, allows the transfer of 1C units for biosynthetic purposes such as de novo synthesis of adenosine, guanosine and thymidylate and for methylation reactions that support the methionine cycle. Metabolic alterations have been exploited by researchers ever since, in order to understand tumour growth and metastatic dissemination. Warburg described an increase in aerobic glycolysis, ‘Warburg effect’, where cancer cells took up and fermented glucose to lactate in the presence of oxygen. The first evidence for changes in cancer metabolism were observed by Otto Warburg during the early 20th century. Such metabolic reprogramming has been extensively studied. Similar content being viewed by othersĬancer cells undergo metabolic changes to harness nutrients and support their rapid growth and proliferation. Additionally, we explore possible therapeutic strategies that could overcome the limitations of traditional antifolates. In this article, we present a detailed overview of folate-mediated 1C metabolism, its importance on cellular level and discuss how targeting folate metabolism has been exploited in blood cancers. Notably, mitochondrial 1C enzymes have been shown to be significantly upregulated in various cancers, making them attractive targets for the development of new chemotherapeutic agents. However, traditional antifolates have many deleterious side effects in normal proliferating tissue, highlighting the urgent need for novel strategies to more selectively target 1C metabolism. Since then, antifolates, such as methotrexate and pralatrexate have been used to treat a series of blood cancers in clinic. Targeting the folate metabolism gave rise to modern chemotherapy, through the introduction of antifolates to treat paediatric leukaemia. Through a number of interlinked reactions happening in the cytosol and mitochondria of the cell, folate metabolism contributes to de novo purine and thymidylate synthesis, to the methionine cycle and redox defence. Folate-mediated one carbon (1C) metabolism supports a series of processes that are essential for the cell.
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