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Editorial Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 149 Editorial

Anti- as a Novel Strategy for Cancer Therapy “Biochemistry textbooks present and fat synthesis as history, with all of facts known” [1]. However, a new challenge emerges with better understanding of cancer cell -aerobic glycolysis is approximately 200 times higher in a cancer cell than in the normal cell of origin, even though is available [2]. is a universal fuel and building material in organisms due to its low non-specific glycation, a process that often leads to damage and dysfunction [3]. Glucose is used for energy (adenosine 5-triphosphate, ATP) production in cells by aerobic or anaerobic respiration. Through the glycolytic pathway, glucose is also diverted to de novo synthesis (lipogenesis) and other biosynthetic pathways (Fig. (1)). Lipogenesis consists of two processes: long chain and triglyceride synthesis (esterification of fatty acids with ). In cytosol, glucose is glycolyzed into pyruvate that is then converted to citrate in mitochondria. Citrate is transported into the cytosol and cleaved into acetyl-CoA and oxaloacetate by ATP citrate lyase. Cytosolic acetyl-CoA is used for malonyl-CoA formation by acetyl-CoA carboxylases. Fatty acid synthase condensates malonyl-CoA and acetyl-CoA into a long chain fatty acid, saturated palmitate (C16:0) [4, 5]. This de novo fatty acid synthesis from glucose is called a glycolysis-citrate-lipogenesis pathway. Glucose

GLUT4

Glycolysis Nucleogenesis ATP, GTP, UTP, Triglyceride, CTP, NAD(P)+ phospholipids

Pyruvate Fatty acids

FAS

Malonyl-CoA Pyruvate ACCA ACL Citrate Citrate Acetyl-CoA

13 Fig. (1). Hypothetic glycolysis-citrate-lipogenesis pathway in cancer cells. Glucose is transported into cells and catabolized into pyruvate via glycolysis pathway. In mitochondria, pyruvate is converted into citrate that enters into cytosol and is converted into acetyl-CoA by ACL. Under catalysis of ACC, acetyl-CoA is carboxylated into malonyl-CoA that is condensated with acetyl-CoA to form long acyl chains by FAS. ACL, ATP-citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase and GLUT4, glucose transporter 4.

ATP citrate lyase (ACL or ACLY; EC 4.1.3.8) is the first enzyme in the de novo lipogenic pathway linking glycolysis to lipogenesis. ACL is an extra-mitochondrial enzyme that cleaves citrate into cytosolic acetyl-CoA, an essential component for fatty acid synthesis [6]. ACL is composed of two subunits in and lower-rank eukaryotes (e.g. fungi), but in mammalian cells it is a 110kDa polypeptide and functions as a homomeric tetramer [7]. Mammalian ACL protein contains five domains that are named, from the N-terminus, domains 3, 4, 5, 1 and 2. ACL activity is regulated at transcriptional and posttranslational levels; the latter is mediated by phosphorylation and dephosphorylation. Acetyl-CoA carboxylases (ACC or ACAC, EC 6.4.1.2) catalyze the rate-limiting carboxylation of acetyl-CoA into malonyl-CoA by two steps: ATP-dependent biotin carboxylation and ATP-independent carboxyl group transfer [8, 9]. In prokaryotic cells, ACC consists of unstable multi- subunits, including biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT). In eukaryotes, however, ACC is a single multi-domain polypeptide that contains a BC domain, a BCCP domain, and a CT domain [10]. The BC domain catalyzes carboxylation of N1 atom in ureido ring of biotin, the BCCP domain acts as a covalent carrier 150 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Editorial of biotin, and the CT domain transfers the carboxyl group from the N1 atom to the methyl group of acetyl-CoA. In humans and other mammals, two ACCs have been identified: ACC1 (also referred to ACC-) with 265kDa and ACC2 (also known as ACC-) with 280kDa. ACC1 and ACC2, encoded by different genes, share 75% amino sequence similarity, but have distinct subcellular distribution and function. ACC2 has an extra 114 amino acids in the N-terminus, where the first 20 residues constitute a signal peptide targeting ACC2 to the mitochondrial membrane [11]. Therefore, ACC1 is mainly expressed in lipogenic tissues (liver, adipose and lactating mammary gland) and its product, malonyl-CoA, is used for the biosynthesis of long-chain fatty acids [12]. In contrast, ACC2 is expressed mostly in the liver, skeletal muscle and heart with high energy metabolic activity. The malonyl-CoA that ACC2 produces mainly participates in the regulation of fatty acid -oxidation by inhibiting carnitine palmitoyltransferase I (CPT-I) activity [13]. Therefore, cellular malonyl-CoA plays a dual role in fatty acid synthesis and oxidation, depending on its subcellular distribution. ACC activity is regulated at the transcriptional and posttranslational levels. Fatty acid synthase (FAS or FASN; EC 2.3.1.85) is a 270kDa multifunctional cytosolic polypeptide catalyzing the condensation of acetyl-CoA and malonyl-CoA to form palmitate. The saturated palmitate is a parental fatty acid from which non-essential fatty acids are produced. FAS consists of seven domains. They are malonyl/acetyltransferase (MAT), beta-ketoacyl synthase (KS), dehydrogenase (DH), enoyl reductase (ER), beta-ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE) [14]. FAS expression is regulated by upstream stimulatory factors and sterol regulatory element binding protein-1 in response to nutrients and insulin [15]. In normal tissues, lipogenesis occurs mainly in the liver and adipose tissues and is tightly regulated by nutrients and hormones, such as growth factor and insulin, through controlling the expression and activity of the lipogenic enzymes [4, 16]. Circulating fatty acids from nutrients are preferentially used [4, 17]. Increased de novo lipogenesis and the resultant positive balance of is a fundamental cause of metabolic syndromes, such as obesity [17, 18]. A potent strategy to tackle this problem is to suppress the de novo lipogenesis by developing small chemical inhibitors that target the lipogenic enzymes, such as ACL, ACCs, or FAS [19-26]. Bioenergetic changes of cancer cells are well known, including increased glucose glycolysis and lipogenesis [27, 28]. In the early 1920s, Nobel laureate Otto Warburg found that cancer cells aggressively consume glucose and produce energy by glycolysis, even in the presence of oxygen [29]. This phenomenon is known as the Warburg effect. However, it has been puzzling why cancer cells rely on an inefficient aerobic glycolysis to generate energy (ATP) until recent understanding that this metabolic alteration is adaptive of the tumor cell to uptake and incorporate nutrients into biomass, such as lipids. Through the glycolysis-citrate-lipogenesis pathway, cancer cells simultaneously meet their energy and synthetic needs for their rapid growth and proliferation [2]. Lipids are essential for the biosynthesis of biomembranes and serves as the second messengers, playing a critical role in cell growth and proliferation. In sharp contrast to normal cells, cancer cells take 95% of fatty acids from de novo synthesis for cellular lipids, even when extracellular fatty acids are abundantly available. Therefore, increased lipogenesis is a hallmark of cancer cells and an early event in tumorigenesis [27, 30-33]. For instance, FAS is upregulated in the earliest stages of prostate neoplastic transformation (PIN lesions) and its expression level is positively correlated to the grades of PIN lesions and invasive carcinomas [27, 32, 34]. Increased activity of the lipogenic enzymes in cancer cells is also reflected in their phosphorylation status [35] and stability [36, 37]. In addition, ACC sequence variants was found to be associated with breast cancer susceptibility [38], further supporting the important role of lipogenesis in tumorigenesis. In addition to meeting the need of lipids for rapid cell growth and proliferation, increased de novo lipogenesis also provides lipids as precursors for oncogenic signaling, contributing to cancer development and progression [31, 39]. In tumor cells, newly synthesized lipids are mainly phospholipids enriched with saturated or monounsaturated fatty acids. Saturated fatty acids tend to partition into detergent resistant microdomains or rafts on membranes, which mediate cell migration, signal transduction, and intracellular trafficking [31, 39, 40]. Therefore, through the increased glycolysis-lipogenesis flux of glucose, cancer cells’ increased needs of lipids for energy, biomass, and oncogenic signaling are all met. Suppression of this aerobic glycolysis- citrate-de novo fatty acid/lipid synthesis axis may be an effective intervention of cancer development and progression. This hypothesis has been supported by studies on the inhibition of lipogenic enzymes and gene silencing induced by RNA interference (RNAi) in cancer cells, inducing cell growth inhibition and apoptosis [41-43]. Up to date, small chemical inhibitors of the lipogenic enzymes have become potential therapeutic agents of cancers. ACL is a central mediator between Warburg effect and lipogenesis in cancer cells by converting citrate produced by glycolysis to acetyl-CoA, an essential component of fatty acid synthesis [44]. ACL expression is widely elevated in human tumors, and inhibition of ACL activity significantly inhibits cancer cell proliferation and suppresses tumor growth [45-47]. In combination with statin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, ACL knockdown blocks mitogen-activated protein kinase (MAPK) signaling pathway and attenuates PI3K/AKT signaling, leading to apoptosis and differentiation of non- small cell lung cancer cells [21]. In addition, ACL may mediate the palmitate-induced apoptosis in pancreatic beta cells [48]. Therefore, various small chemical ACL inhibitors have been developed, such as arylchalco-genoarylalkylsubstituted imidazolidine-2,4diones (Patent application No.: US20110046185) [49], heterocycle-substituted imidazolidine-2,4-diones (Patent application No.: US20110046105) [50], and SB-201076 (Patent No.: WO9322304) [51]. These are representative new patents/patent applications. Please refer to the article in this Hot Topic issue for more details. Malonyl-CoA production is the rate-limiting step in fatty acid synthesis catalyzed by ACC. Similarly, various ACC chemical inhibitors have been identified as herbicides in agriculture and agents for the treatment of microbial infections, diabetes, obesity and cancer [19, 20, 36, 37, 52-54], such as spirochromanone derivatives (Patent No.: US7935712) [55], Editorial Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 151 cyclohexane derivatives (Patent application No.: WO2011067306) [56], aryl amide compound (USPTO application No.: US20100113473) [57], 1-[2-(4-phenoxyphenoxy)-1,3-benzothiazol-6-yl], and 1-[2-(4-phenoxyphenoxy)-1,3- benzothiazol-6-yl]ethanamine and 2-[2-(4--phenoxyphenoxy)-1,3-benzothiazol-6-yl]propanenitrile (USPTO Application No.: US20090048298) [58]. Recently, orally active (4-piperidinyl)-piperazine derivatives were reported as potent ACC1/2 inhibitors (patent information unavailable yet) [59]. An article is enclosed in this Hot Topic issue for a detailed introduction. FAS is considered as a metabolic oncogene [60, 61] and profoundly affects cancer cell growth and survival [42, 62-65]. For instance, inhibition of FAS induces ubiquitin-dependent degradation of PI3K signaling and cell death [66]. In addition, FAS also mediates homeostatic response to myocardial stress and coxsackievirus B3 replication [67, 68], which broadens the use of FAS inhibitors. The most recent patents/patent application published include triazoles (Patent application No.: US20110274654) [69], tetrazolones (Patent application No.: US20110274655) [70], and epigallocatechin-3-gallate (Patent No.: US6652890) [71]. BI 99179 is a new FAS inhibitor, but yet its patent information is unavailable [72]. Please refer to the article in this Hot Topic issue for more details. Small chemical compounds can be designed to be readily taken up by cells, but their specificity is a potential concern. Often, interaction with non-intended targets leads to undesirable side effects. Recently, oligonucleotides that can inhibit the expression of specific genes have been developed as a novel tool for research and being explored as therapeutic agents for cancer. These oligonucleotide agents are classified into antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and microRNAs [73-77]. These oligonucleotide agents are highly specific towards their target genes, and they can be readily designed from the known DNA/cDNA sequences. Knowledge of protein structure is not needed and large scale screening for lead compounds is unnecessary. With recent improvements on their stability and cellular uptake, the oligonucleotide agents hold great promise. For instance, RNA interference molecules that mediates small RNA (Patent application No.: US20110112283) [78] and RNA sequence-specific mediators (Patent application No.: US20110244446) [79] are recently patented. Oligonucleotides that are fatty acid synthetic enzymes are also patented, such as ACC antisenses (Patent application No.: US20090137513 and US20050124568) [80, 81] and FAS antisense (Patent application No.: US20040077570) [82]. More detailed discussion is included in an article in this Hot Topic issue. In summary, malignancy is a leading cause of human deaths, and recent evidence shows that lipogenesis plays a critical role in the tumor development and progression by providing energy and synthetic needs for cancer cells. Various small chemical inhibitors and antisense agents that modulate the activity of lipogenic enzyme have been developed and patent protections have been issued. This hot topic issue of Anti-Lipogenesis as a Novel Strategy for Cancer Therapy is dedicated to the discussion of the patents on chemicals and antisense oligonucleotide agents that target lipogenic enzymes for the treatment of cancer.

ACKNOWLEDGEMENTS This work was supported in part by Department of Defense Breast Cancer Research Program (BC083555) for D. C. and National Natural Science Foundation of China (No.81170807) for J. L.

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Jianghua Liu Deliang Cao Department of Metabolism and Endocrinology, Department of Microbiology, Immunology and The First Affiliated Hospital, Cell Biology, Simmons Cancer Institute, University of South China, Southern Illinois University School of Medicine. 69 Chuanshan Road, Hengyang, 913 N. Rutledge Street, Hunan 421001, Springfield, IL 62794, P.R. China USA E-mail: [email protected]