Anti-Cancer Drugs Targeting Fatty Acid Synthase (FAS)

Abstract

Fatty acid synthase (FAS) is a key enzyme of the fatty acid biosynthetic pathway which catalyzes de novo lipid synthesis. FAS expression in normal adult tissues is generally very low or undetectable as majority of fatty acids obtained are from dietary sources, whereas it is significantly upregulated in cancer cells despite adequate nutritional lipid supply. Activation of FAS provides rapidly proliferating tumor cells sufficient amount of lipids for membrane biogenesis and confers growth and survival advantage possibly acting as a metabolic oncogene. Importantly, inhibition of FAS in cancer cells using the pharmacological FAS inhibitors results in tumor cell death by apoptosis whereas normal cells are resistant. Due to this differential expression of FAS, the inhibitors of this enzyme are selectively toxic to tumor cells and therefore FAS is considered an attractive therapeutic target for cancer. Several FAS inhibitors are already patented and commercially available; however, the potential toxicity of these FAS inhibitors remains to be tested in clinical trials. In this review, we discuss some of the potent FAS inhibitors along with their patent information, the mechanism of anti-cancer effects and the development of more specific and potent FAS inhibitors with lower side effects that are expected to emerge as anti-cancer treatment in the near future.

Identification of proteomic and metabolic signatures associated with chemoresistance of human epithelial ovarian cancer

“…Profiling of metabolomics elucidated changes in the levels of fatty acid metabolism, which confirmed our previous observations by proteome approach and conclusions of many addressed articles on chemotherapeutic resistance and metabolism, and served as an insightful reference to the mechanism research of drug resistance. Fatty acid synthese (FASN) providing proliferating cancer cell lipids for membrane biogenesis was assumed to have metabolic characteristics of cancel cells (45). Expression level of FASN is significantly upregulated in kinds of neoplasm and correlates with poor prognosis, but in a health individual is very low even undetectable, suggesting that FASN serves as a metabolic oncogene (46).…”

Carnitine palmitoyltransferase 1C: From cognition to cancer

“…This increased glycolysis also allows the diversion of glucose into the pentose phosphate pathway to produce NADPH and regenerate the reduced anti-oxidant glutathione [107] and to promote the diversion of glycolytic intermediates into various biosynthetic pathways, including those generating nucleosides and amino acids; this facilitates, in turn, the biosynthesis of the macromolecules and organelles required for the assembly of new cells; ii) a change of glutamine metabolism by redirecting glutamine carbon to also support biosynthetic pathways such as nucleosides and amino acids and to maintain redox homeostasis [108]; and iii) a change in lipid metabolism (for general reviews see [109][110][111]). The cancer cell develops a lipogenic phenotype that increases de novo FA synthesis [109,112,113]. In addition, under conditions of metabolic stress, some tumors scavenge lipids from their environment to maintain viability and growth [114,115].…”

Uncovering metabolism in rhabdomyosarcoma

“…[10][11][12][13] In addition to dependency on glutaminolysis, the majority of human cancers, including breast, colon, ovary, lung, and prostate tumors express high levels of fatty acid synthase (FAS), a key metabolic enzyme that is functional to catalyze the synthesis of long chain saturated fatty acids for supporting the increased demand for membrane biogenesis. 14,15 The therapies currently employed to limit tumor expansion mostly utilize cocktails of antineoplastic drugs that interfere with the cell cycle progression; these agents include cell cycle specific drugs like plant alkaloids (etoposide, topotecan) or DNA synthesis inhibitors (5-fluorouracil, methotrexate) and cell cycle non-specific drugs like crosslinking agents (cyclophosphamide, ifosfamide, cisplatin) or intercalating anthracycline antibiotics (doxorubicin, daunorubicin). Some of them, such as doxorubicin, cisplatin and the anti-tumor peptide actinomycin, are also known to trigger cell death by increasing the reactive oxygen species (ROS) levels through various mechanisms.…”