Rate-limiting lipases, including acetyl-Coa carboxylase (ACC), fatty acid synthase (FAS), ATP-citrate lyase (ACLY), and stearoyl Coa desaturase (SCD). Lipids, including fats, waxes, sterols, and fat-soluble vitamins. In recent years, there have been significant advances in our understanding of the role of lipids in the process of carcinogenesis, the process by which normal cells transform into cancer cells1. Tumors occur when normal cells evade the processes that control their growth. Long-standing studies have shown that cancer cells are characterized by increased lipid synthesis, mainly because lipids are needed for the cell's membrane, so it is logical to develop cancers that target the rate-limiting step of the lipidogenic response. There is a good review on the relationship between lipid metabolism and cancer, with a great deal of background information and detailed illustrations2, and another review that provides additional insight into the prospects and challenges of lipidogenic inhibitors.3 This newsletter will focus on the latest advances in lipidase inhibitors for cancer.
1.Lipid metabolism in cancer cells.
Lipids are synthesized in adipocytes and liver cells, and some of these lipids, such as linolenic acid and linoleic acid, cannot be manufactured de novo by mammals and need to be obtained from food. Cancer cells tend to make their own lipids, which allows them to bypass some of the growth restrictions imposed on other cells. They do this with the help of elevated levels of rate-limiting lipases such as acetyl-Coa carboxylase (ACC), fatty acid synthase (FAS), ATP-citrate lyase (ACLY), and stearoyl Coa desaturase (SCD)4. In addition to cell growth, tumors utilize lipids in a variety of ways, including oncogenic signaling, which highlights the complexity of lipid metabolism in cancer. Tumor cells increase the production of new fat, the uptake of fatty acids, and the oxidation of fatty acids to produce energy and accumulate fat. Cancer regulates ferritin deposition-mediated cell death, supports metastasis, and interacts with the tumor microenvironment by altering lipid metabolism2. Unfortunately, healthy tissues, especially those in the immune system, also require lipids, which limits the utility of general metabolic inhibitors5.
Figure 1: Schematic diagram of fatty acid synthesis and key enzymes that may be potential drug targets.
2 Acetyl-Coa carboxylase.
Acetyl-CoA carboxylases (ACCs) have two isoforms: ACC1 and ACC2, also known as ACC and ACC2, which are core enzymes of mammalian metabolism and mediate fatty acid synthesis, glycolysis, and other carbon conversions (Figure 1). ACCs convert acetyl-CoA to malonyl-CoA6, enzymes that promise to be targets for cancer**. ACC levels are elevated in some cancer cells, and some small molecule inhibitors have entered different stages of clinical trials. ND-646 can block both isoforms, thereby preventing the development of non-small cell lung cancer7,8. Liver-specific ND-654 was tested in mice and found to reduce hepatocellular tumors11. When these inhibitors were tested in conjunction with standard chemotherapy, they were more effective at inhibiting tumor growth than without the combination8,9. For more information on the role of ACCs in disease regulation, see a recent review by Wang et al.10.
3.Fatty acid synthase.
Fatty acid synthase (FAS) is another attractive target for anti-cancer inhibition by the successive addition of acetyl groups to construct lipid carbon chains, which ultimately produce palmitate (Figure 1). Upregulation of this enzyme has been implicated in a variety of cancers, and the FAS inhibitor Fasnall inhibits breast cancer in mouse models, either alone or in combination with carboplatin11. However, fasnall exemplifies the complexity of targeting a single metabolic pathway for cancer**, which appears to reduce in half the number of in vitro breast cancer tumors but increases the other half, leading to the suggestion that multiple metabolic pathways need to be targeted as a supplement to the norm12. Omeprazole, an over-the-counter medication that can be used to control heartburn, is a mild FAS inhibitor that is rarely used and has therefore been reused for cancer. It is currently being used in clinical trials for a variety of cancers2. Small interfering RNA (siRNA) is a small fragment of RNA that specifically inhibits protein production by binding to and inactivating a specific mRNA. One of the siRNAs, which targets FASN translation, has shown promising results in tumor reduction in mouse models. A recent review described fatty acid metabolism against stressed cancer cells13.
4.ATP-citrate lyase.
ATP-citrate lyase (ACLY) converts citrate to acetyl-Coa and oxaloacetate (Figure 1). This enzyme is highly expressed in a variety of cancers, including lung cancer14 and liver cancer15, and inhibition of this enzyme inhibits cancer16. A recent review dedicated to the clinical and preclinical use of ACLY inhibitors as cancer**17. The ACLY inhibitor BMS-303141 successfully inhibits hepatocellular carcinoma (HCC)18. The small molecule ACLY inhibitor ETC-1002 has been intensively studied in clinical trials for a variety of non-cancer diseases. ETC-1002 is modified in the liver, which is important for its activity9. Tissue specificity is a desirable property for anticancer drugs, and ETC-1002 in combination with the FGFR1 inhibitors PD173074 or PD-L1 can reduce the occurrence of hepatocellular carcinoma20. Gut microbiota-derived acetyl-Coa bypasses ACLY inhibition, which is particularly important in HCCA21. However, ETC-1002 can also activate AMPK, which slows adipogenesis by inhibiting acetyl-CoA carboxylase19. Therefore, ETC-1002 deserves further study.
5.Stearyl-Coa desaturase.
Palmitic acid is a rich saturated fatty acid that can be absorbed by stearoyl-Coa unsaturase (SCD;).Figure 1) desaturation and generation of palmitoleic acid22. The ratio of saturated to unsaturated fatty acids is in a delicate equilibrium in tumor cells, and disrupting this balance can kill tumor cells23,24. Tumors tend to grow faster than normal blood vessels form, which requires tumors to form new blood vessels for nutrients and oxygen. The depletion of oxygen in cells leads to insufficient synthesis of unsaturated fatty acids, which leads to cell death25. New SCD inhibitors are in preclinical cancer trials, in which MF-438 and CAY 10566 can reduce the occurrence of ovarian cancer by altering membrane phospholipid composition26. While A939572 reduces the growth of primary melanoma, it increases lung metastases27, suggesting how our metabolic pathways are interrelated.
6.Future Prospects: Liposome Enzymes and Cancer Cell Metastasis.
The process of metastasis of cancer cells is a complex process, and few cells can complete the metastasis. Cells capable of completing metastasis are dependent on lipid metabolism, but data on the effects of these lipinases on metastasis are complex. For example, inhibition of ACCs increases levels of ACYTL-CoA, which may inhibit ACC1-stimulated breast cancer metastases28. Some cancers that metastasize to the brain choose areas that are deficient in lipids because these cancer cells can make their own lipids;Therefore, targeted FAS is effective in preventing the survival of breast cancer cells that have metastasized to the brain29. In general, cancer cells are characterized by elevated lipid metabolism, which is controlled by the enzyme tachylipase. Unfortunately, healthy cells also need lipids, so our goal is to slow down, rather than stop, the activity of these key enzymes, which tends to slow down cancer growth. Inhibition of changes in lipid metabolism through small molecule inhibitors has become a promising area of cancer research2.
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