Ann. N.Y. Acad. Sci.

ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

Issue: Toward Personalized Medicine for Cancer

Novel anti-fatty acid synthase compounds with anti-cancer

activity in HER2+ breast cancer
G. Oliveras,1 A. Blancafort,1 A. Urruticoechea,2 O. Campuzano,1 D. Gómez-Cabello,3
R. Brugada,1 M. L. López-Rodrı́guez,4 R. Colomer,3 and T. Puig1
1
Institut d’Investigació Biomèdica de Girona – Facultat de Medicina, Girona, Spain. 2 Institut Català d’Oncologia, Institut
d’Investigació Biomèdica de Bellvitge, Barcelona, Spain. 3 Centro Oncológico MD Anderson España, Madrid, Spain. 4 Quı́mica
Orgánica I, Facultad de Ciencias Quı́micas, Universidad Complutense, Madrid, Spain

Address for correspondence: Teresa Puig, Institut d’Investigació Biomèdica de Girona, Universitat de Girona, Girona, Spain.
[email protected]

Fatty acid synthase (FASN) expression and activity has emerged as a common phenotype in most human carcinomas,
including breast cancer, and its expression is tightly linked to HER2 signaling pathways. The development of inhibitors
of FASN activity has consequently appeared as a novel antitarget modality for treating cancer. However, the clinical
use of FASN inhibitors, such as cerulenin, C75, and epigallocatechin 3-gallate (EGCG), is limited by anorexia and
induced body weight loss or by its low in vivo potency and stability. Here, we summarize the design and development
of G28UCM, the lead-compound of a novel family of synthetic FASN inhibitors, with both in vitro and in vivo activity
in a human breast cancer model of FASN+ and HER2+ .

Keywords: breast cancer; fatty acid synthase (FASN); novel anti-FASN compounds; HER2; preclinical study

FA are present as metabolic substrates in nor-

New approaches to cancer treatment:
mal cells and are restored as triglycerides (TG) in
lipogenesis and cancer
adipose tissue. The body’s pool of FA comes from
Since the 1920s, cancer cells have been known to ex- different sources, both exogenous (e.g., dietary FA)
hibit an altered metabolism; currently, it is known and endogenous, including both the hydrolysis of
that this point is crucial for both cancer cell survival TG (from adipose tissue) and the lipogenic path-
and anticancer drug development. One hallmark way (de novo synthesis). Thus, this constitutes one
of malignant cells is their higher rate of energy- of the important metabolic differences between nor-
consuming processes due to the increased protein mal and cancer cells. While most human tissues pre-
and DNA synthesis needed to maintain cell divi- fer using exogenous lipids for the synthesis of new
sion.1 In 1924, Warburg and colleagues observed structural lipids (including phospholipids, TG, and
that cancer cells consume glucose through an anaer- cholesterol esters), and so fatty acid synthase (FASN)
obic pathway in order to produce lactic acid (the expression is low, it has been reported that in cancer
Warburg effect),2 providing malignant cells with an cells, FA were derived mainly from de novo synthe-
advantage in the tumor microenvironment.3 This sis.5 The imperative need of cancer cells to synthe-
enhanced anaerobic glycolysis produces an excess of size FA has promoted the selection of two regula-
pyruvate that is transformed into lactate and acetyl- tory enzymes—FASN and acetyl-CoA carboxylase
CoA. The high proliferation ratio of cancer cells in- (ACC)—and one intermediate enzyme, malonyl-
creases their need for fatty acids (FA) as substrates CoA, as drugable targets as a new approach to can-
for the biosynthesis of phospholipids, which are es- cer treatment. Accordingly, FASN expression and
sential constituents of biological membranes and are activity have emerged as a common phenotype in
involved in protein acylation and energy production most human cancer cells and is mostly absent in
through ␤-oxidation.4 the corresponding normal cells.6 Since the 1990s,

doi: 10.1111/j.1749-6632.2010.05777.x
86 c 2010 The New York Academy of Sciences
Ann. N.Y. Acad. Sci. 1210 (2010) 86–93 
Oliveras et al. Fatty acid synthase and cancer

mounting evidence has pointed to an important ERK1/2) pathways that modulate the expression
role of FASN in cancer cell survival, progression, and maturation status of the transcriptional factor
and malignity. FASN has emerged as a prognosis sterol response element binding proteins (SREBP-1)
biomarker in breast, prostate, and other carcinomas to produce SREBP-1c, which modulates FASN gene
and we have shown that its inhibition is specifically maturation and expression15 (Fig. 1A).
cytotoxic for human cancer cells.5,7 Although part The first signal that FA in cancer cells were due
of these effects could be due to the accumulation of to de novo synthesis was sent out in the 1950s, when
malonyl-CoA,8 similar effects have been observed Medes and colleagues16 determined that most of
by inhibiting other lipogenic enzymes, suggesting the FA esterified in tumors were FASN products
that lipogenesis has an important role in the can- (approximately 93% of FA originated from TG).
cer physiopathology.9 In summary, FASN plays an In general, cancer cells are characterized by an ex-
essential role in energy homeostasis and could be a acerbated anaerobic glycolysis accompanied by an
good target for the development of both anti-obesity activation of the glycolytic enzymes2 and also by
and anticancer agents. an increased level of synthesis of FA that corre-
lates with an overexpression and hyperactivity of
FASN expression and regulation in normal
lipogenic enzymes such as FASN.17 This pheno-
and cancer cells
type seems to give to malignant cells an advan-
FASN (E.C.2.3.1.85) is a homodimeric multien- tage for survival and growth in the microenviron-
zymatic protein of 250–270kD divided into seven ment of biological and metabolic tumors.18 FASN
functional domains, assembled into two homod- overexpression and hyperactivation have been de-
imers.10 Through a series of 32 reactions, FASN is scribed in many cancers and commonly correlate
able to synthesize long chain fatty acids (LCFA), with a higher rate of recurrence and a lower chance
mainly palmitate, using acetyl-CoA and malonyl- of survival.19 Using immunohistochemistry anal-
CoA as substrates and NADPH as an electron ysis, high levels of FASN have been observed in
donor.11 many preneoplasic lesions, including breast, pan-
FASN is expressed mainly in lipogenic tissues, in creas, prostate, colon, and lung cancer. The pathways
some hormone-sensitive cells (e.g., lactating mam- responsible for FASN overexpression in cancer cells
mary glands, cycling endometrium, and seminal are not yet well understood. Four different mecha-
vesicles), in various specialized cell types (type II nisms have been proposed: enhanced transcription,
alveolar cells to produce surfactant, hypothalamus increased translation, greater stability of proteins,
to control food intake), and in proliferating fetal and gene amplification.7 These mechanisms may
cells.12,13 In adults, lipogenesis is required primarily be active at the same time and may prevent FASN
for the following: (1) to store excess of energy from its physiological regulation, thus resulting in
ingested as carbohydrates by generating TG; (2) to a constitutive activation of the lipogenic pathway
synthesize fat from other substrates (carbohydrate in tumors. FASN regulation at the transcriptional
or protein) in fat-deficient diets; or (3) to produce level is one of the most studied mechanisms. It in-
FA in special tissues or situations such as the volves mainly growth factors/growth factor recep-
synthesis of medium chain fatty acids in lactation. tors (GF/GFR) and steroid hormones/steroid hor-
Taking into account these functions, the role of mone receptors (SH/SHR), although new players
FASN in a well-nourished population is not of great such as hypoxia-inducible factor 1 (HIF-1␣) and
significance, as dietary lipids cover the requirements p53 family members have recently been implied in
to maintain homeostasis.14 In normal cells, FASN the regulation of FASN expression. It is important
expression remains at low levels and its regulation is to notice that at the transcriptional level, the ex-
complex and highly dependent on nutritional status pression of FASN in both normal and cancer cells
and on the hormonal profile.11 To summarize, FASN occurs in most cases through the same signaling
is activated by nutritional status and its expression pathways (PI3K/AKT/mTOR and MAPK/ERK1/2)
is mediated by different signaling pathways, such by promoting the binding of SREBP-1c to its re-
as the phosphoinositide-3 kinase/protein kinase sponding elements in the FASN promoter. The main
B (PI3K/Akt) and mitogen-activated protein ki- difference between normal and cancer cells is the
nase/extracellular signal-regulated kinase (MAPK/ stimuli that activate the signaling cascades (Fig. 1B).

c 2010 The New York Academy of Sciences

Ann. N.Y. Acad. Sci. 1210 (2010) 86–93  87
Fatty acid synthase and cancer Oliveras et al.

Figure 1. FASN regulation in normal and cancer cells. (A) FASN expression in normal cells is dependent on nutritional and
hormonal status. FASN transcription is upregulated by food intake, fatty acids (FA), or hormones and downregulated by polyun-
saturated fatty acids (PUFAS), cAMP, or fasting (glucagon). These stimuli activate different cascades, such as the phosphoinositide
3-kinase/protein kinase B (PI3K/AKT) or mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK1/2)
pathways, which finally modulate the expression and maturation status of the sterol regulatory element-binding protein 1C (SREBP-
1C). The active form of SREBP1C is translocated into the nucleus where it can bind to the FASN promoter responding elements.
(B) In cancer cells, the growth factors (GF) or steroid hormones (SH)—esterols, androgens or progesterone—lead, through their
receptors (GFR/SHR), to downstream PI3K/AKT, MAPK/ERK1/2, or mTOR signaling pathways by, finally, promoting the binding
of SREBP-1C to its responding elements in the FASN promoter region. FASN expression in cancer cells is also activated by the
tumor microenvironment (hypoxia and acidosis) through the upregulation of the hypoxia-inducible factor 1␣ (HIF-1␣), which
induces the AKT activation. Other proteins, such as p53 or SPOT14, are able to increase FASN transcription. FASN expression can
also be achieved at the posttranslational level through interaction with USP2a, a preproteasomal ubiquitin-specific protease that,
by removing ubiquitin from FASN, strongly stabilizes FASN protein. All these pathways can occur simultaneously in cancer cells.
(Figure taken from Relat & Puig.41 )

In cancer cells, FASN is insensitive to nutritional cells, and it has been demonstrated that FASN plays
signals and SREBP-1c expression and activation is an essential role in tumor growth and survival.20
driven by aberrant GF/GFR and SH/SHR levels or In prostate and breast cancer, several studies have
impaired signaling pathways.5,18 demonstrated an association between FASN expres-
sion and the prognosis of the disease. In stage I breast
FASN: a biomarker and a druggable target
cancer, patients with high levels of FASN show a
FASN expression and activity have been shown to fourfold increased risk of death from this pathology
be a common phenotype in most human tumor than patients with lower FASN protein levels.21 In

88 c 2010 The New York Academy of Sciences

Ann. N.Y. Acad. Sci. 1210 (2010) 86–93 
Oliveras et al. Fatty acid synthase and cancer

Figure 1. Continued.

prostate cancer, FASN expression correlates with a impairs their DNA synthesis and cell cycle progres-
fourfold risk of recurrence and an increased Glea- sion. Many efforts have been made into developing
son grade and risk of death from the disease. It has pharmacological anti-FASN activity compounds. At
been shown that this risk raises up to 12-fold when a molecular level, different pathways have been
PTEN is deleted.22 FASN expression has also been modified by FASN inhibition and it has been shown
associated with HER2 expression in poor prognosis that cancer cell death can also be increased if FASN
tumors.23 Recently, an ELISA assay has been devel- inhibitors are combined with inhibitors of FASN-
oped to show the positive correlation between cir- related signaling cascades (e.g., PI3K/AKT, HER2,
culating levels of FASN and the disease’s degree.24 and mTOR).22,25 In addition to cell arrest, FASN
However, further studies will be necessary to deepen inhibition causes cancer cell death.26 The inhibi-
in the role of FASN expression in the cancer prog- tion of FA synthesis using siRNA against FASN or
nosis and the usefulness of determining FASN in ACC reduces the incorporation of phospholipids
serum or in tumor samples as pathologic markers into membranes, causing morphological changes in
for diagnoses or for predicting the progression of cells and ultimately leading to apoptosis of breast
the disease. and prostate cancer cells without affecting nonma-
Recent studies have sought to describe the effect lignant cells.8 It has been observed that FASN in-
of FASN activity inhibition on the cell cycle status. hibition (using siRNAs or small molecules) causes
The fact is that the disruption of de novo FA synthesis ER stress and activation of an unfolded protein

c 2010 The New York Academy of Sciences

Ann. N.Y. Acad. Sci. 1210 (2010) 86–93  89
Fatty acid synthase and cancer Oliveras et al.

Figure 2. Chemical structure of the FASN inhibitors.

response (UPR), inducing cell death.27 FASN inhi- structurally related synthetic molecules were devel-
bition also causes an increase of malonyl-CoA levels oped: C75 and C93.26,29 C75 is a cerulenin-derived
that could result in an accumulation of malonyl- compound that lacks the reactive epoxi group
CoA or toxic lipid intermediates that finally induce (Fig. 2).29 C75 was initially synthesized as an
cell death.8 Finally, FASN overexpression is associ- inhibitor of mammalian FASN and structurally
ated with the palmitoylation of signaling proteins, related to malonyl-CoA. Although initially it
so that the interference of this pathway may also provides the first evidence of in vivo growth tumor
induce apoptosis.28 reduction after FASN inhibition,29 its clinical devel-
In summary, many reasons point to FASN as opment as an antitumor agent has been discarded
a novel druggable target against cancer. Thus, owing to the side effects produced. The use of C75
many efforts have been put toward developing in- in vivo is limited by anorexia and body weight
hibitors of FASN activity as novel anticancer com- loss, which we and others have associated with
pounds, alone or combined with other anticancer the stimulation of carnitine palmitoyltransferase-1
drugs. (CPT-1), the enzyme responsible for the regulation
of mitochondrial fatty acid oxidation.30 C93 is
Preclinical development of FASN inhibitors
a C75 analogue that blocks the KS domain of
The most studied FASN inhibitors are cerulenin FASN without stimulating FA oxidation or causing
and its synthetic derivative C75 (Fig. 2). Ceru- body weight loss.31 This improvement makes it
lenin [2S,3R)-2,3-epoxi-4-oxo-7,10-dodecadien possible to treat animals more frequently than
oxylamide] is a mycotoxin metabolite derived with C75 and also increases the effectiveness of the
from Cephalosporium caerulens,14 which covalently treatment. Another advantage of C93 is that it can
blocks the ␤-ketoacyl synthase activity (KS) of be administered orally.32 Orlistat is a ␤-lactone
FASN, thus avoiding condensation between the that was first approved as an anti-obesity drug.
acyl intermediate and malonyl-CoA. It has been Orlistat targets gastrointestinal lipases and inhibits
reported that cerulenin is able to delay the progres- FASN by blocking its TE activity domain, which
sion of breast, ovarian, and prostate human cancer is responsible for releasing palmitate.33 Although
xenografts.29 Because of the cerulenin chemical it has been demonstrated that Orlistat inhibits the
instability caused by a reactive epoxi group and growth of a prostate tumor xenograft,34 its poor
the poor systemic availability of cerulenin, two solubility and bioavailability seem to limit the

90 c 2010 The New York Academy of Sciences

Ann. N.Y. Acad. Sci. 1210 (2010) 86–93 
Oliveras et al. Fatty acid synthase and cancer

Table 1. Structure and biological activity of novel polyphenolic compound

EGCG G28UCM
Cancer cell cytotoxicity (IC50 (␮M))
[FASN/HER2 expression levels]
Inhibition of FASN
Compound AU565 [+++] MCF-7 [+] MDA-MB-231 [±] activity (% of control)

EGCG 190 ± 20 205 ± 7 197 ± 15 20

G28UCM 30 ± 5 46 ± 18 79 ± 4 90

use of orlistat as an antitumor drug. It has also conditions,13 which may be illustrated by the lim-
been observed that Orlistat suppresses endothelial ited activity of green tea in prostate cancer clinical
cell proliferation and angiogenesis by inhibiting trials. Based on the chemical structure of EGCG,
FASN.35 we have recently reported the synthesis and bio-
Polyphenols constitute a wide group of differ- logical evaluation of a new series of polyphenolic
ent molecular structures: catechins, flavones, antho- derivatives, which has resulted in the identification
cyanidins, anthraquinones, lignans, coumarins, and of two potent FASN inhibitors with high antitu-
tannins. Some tea polyphenols (black tea and green mor activity in vitro.39 Novel compounds were se-
tea) are able to control body weight, inhibit cancer lected based on their FASN activity inhibition and
cell growth, diminish fat accumulation in the liver their selective cancer cell cytoxicity in a panel of hu-
and blood, and act as antioxidants. These polyphe- man breast cancer cells composed by AU565, MCF-
nols function through many different mechanisms, 7, and MDA-MB-231, as in vitro models of high
including the following: inducing apoptosis, stim- (+++), moderate (+), and low (±) levels of FASN
ulating lipid metabolism, inhibiting lipases, regu- expression, respectively. We observed that two of the
lating thermogenesis, controlling food intake, and novel polyphenolic compounds were quite superior
blocking FASN activity.35 to EGCG in terms of cancer cytotoxicity and FASN
Polyphenolic catechins are the main components activity inhibition.40 Among them, G28UCM was
of green tea and include epicatechin (EC), epicate- selected because of its high FASN activity inhibition,
chin 3-gallate (ECG), epigallo-catechin (EGC), and its potent and selective cancer cell cytotoxicity (Table
epigallocatechin-3-gallate (EGCG), which is consid- 1), its ability to induce apoptosis in a FASN/HER2+
ered the main player in relation to the therapeutic breast cancer model, and finally its marked inhi-
properties of green tea and is also the most abundant bition of HER2-related signaling pathways com-
variety (Fig. 2). Recent studies have reported that pared to EGCG.40 We have preformed preliminary
EGCG, the main polyphenolic catechin of green tea, experiments to evaluate the pharmacological inter-
and other naturally occurring flavonoids (such as action between G28UCM and different anti-HER
luteolin, quercetin, and kaempferol) inhibit FASN, agents against FASN+ and HER2+ breast cancer
induce apoptosis of several tumor cell lines in vitro, cells (AU565 cells), and the potential effectiveness of
and reduce the size of mammary tumors in ani- G28UCM in an in vivo animal study of breast cancer
mal models.36 We have recently reported a simul- FASN+ /HER2+ xenograft. Preliminary results in-
taneous comparison of the cellular, molecular, and dicate that intraperitoneal G28UCM treatment (40
functional effects on the key fatty acid metabolism mg/kg/day) of animals exhibited marked tumor vol-
enzymes FASN and CPT-1 of C75 versus EGCG ume reduction compared with the vehicle treated
in breast cancer cells.9,37,38 We showed that EGCG control animals without any changes in FASN pro-
achieves all cellular, functional, and molecular an- tein expression analyzed by immunohistochemistry.
titumor effects of known FASN inhibitors but, un- Importantly, no significant weight loss or anorexia
like C75, it did not increase CPT-1 activity. How- was identified after 45 days of daily G28UCM-
ever, the in vivo effect of EGCG might be limited treatment in the experimental group. Hematoxylin-
by its IC50 value, as well as its relative instability eosin and picrosirius red stains of the myocardium
under the slightly neutral or alkaline physiological showed no significant structural alterations between

c 2010 The New York Academy of Sciences

Ann. N.Y. Acad. Sci. 1210 (2010) 86–93  91
Fatty acid synthase and cancer Oliveras et al.

the control and G28UCM-treated animals (work in 16. Szutowicz, A., J. Kwiatkowski & S. Angielski. 1979. Lipo-
progress). Our preliminary findings provide a ratio- genetic and glycolytic enzyme activities in carcinoma and
non-malignant diseases of the human breast. Br. J. Cancer
nale for the preclinical development of G28UCM,
39: 681–687.
alone or in combination, as a suitable new agent for 17. Menendez, J.A. & R. Lupu. 2007. Fatty acid synthase and
treating HER2-overexpressing breast cancer. the lipogenic phenotype in cancer pathogenesis. Nat. Rev.
Cancer 7: 763–777.
Conflicts of interest 18. Visca, P., V. Sebastiani, C. Botti, et al. 2004. Fatty acid syn-
The authors declare no conflicts of interest. thase (FASN) is a marker of increased risk of recurrence in
lung carcinoma. Anticancer Res. 24: 4169–4173.
References 19. Puig, T., R. Porta & R. Colomer. 2009. Fatty acid synthase: a
new anti-tumor target. Med. Clin. 132: 359–363.
1. Clemens, M.J. 2004. Targets and mechanisms for the regu- 20. Wang, Y., F.P. Kuhajda, J.N. Li, et al. 2001. Fatty acid syn-
lation of translation in malignant transformation. Oncogene thase (FASN) expression in human breast cancer cell culture
23: 3180–3188. supernatants and in breast cancer patients. Cancer Lett. 167:
2. Warburg, O. 1956. On the origin of cancer cells. Science 123: 99–104.
309–314. 21. Bandyopadhyay, S., S.K. Pai, M. Watabe, et al. 2005.
3. Kuhajda, F.P. 2000. Fatty-acid Synthase and human cancer: FASN expression inversely correlates with PTEN level in
new perspectives on its role in tumor biology. Nutrition 16: prostate cancer and a PI 3-kinase inhibitor synergizes with
202–208. FASN siRNA to induce apoptosis. Oncogene 24: 5389–
4. Kuhajda, F.P. 2006. Fatty acid synthase and cancer: new ap- 5395.
plication of an old pathway. Cancer Res. 66: 5977–5980. 22. Zhang, D., L.K. Tai, L.L. Wong, et al. 2005. Proteomic study
5. Milgraum, F.P., L.A. Witters, G.R. Pasternack & F.P. Kuhajda. reveals that proteins involved in metabolic and detoxification
1997. Enzymes of the fatty acid synthesis pathway are highly pathways are highly expressed in HER2/neupositive breast
expressed in situ breast carcinoma. Clin. Cancer Res. 3: 2115– cancer. Mol. Cell Proteomics 4: 1686–1696.
2120. 23. Wang, Y., F.P. Kuhajda, L.J. Sokoll & D.W. Chan. 2001. Two-
6. Swinnen, J.V., K. Brusselmans & G. Verhoeven. 2006. In- site ELISA for the quantitative determination of fatty acid
creased lipogenesis in cancer cells: new players, novel targets. synthase. Clin. Chim. Acta. 304: 107–115.
Curr. Opin. Clin. Nutr. Metab. Care. 9: 358–365. 24. Liu, X., Y. Shi, V.L. Giranda & Y. Luo. 2006. Inhibition of the
7. Thupari, J.N., M.L. Pinn & F.P. Kuhajda. 2001. Fatty acid phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA
synthase inhibition in human breast cancer cells leads to MB468 human breast cancer cells to cerulenin-induced
malonyl-CoA-induced inhibition of fatty acid oxidation and apoptosis. Mol. Cancer Ther. 5: 494–501.
cytotoxicity. Biochem. Biophys. Res. Commun. 285: 217–223. 25. Pizer, E.S., C. Jackisch, F.D. Wood, et al. 1996. Inhi-
8. Brusselmans, K., E. De Schrijver, G. Verhoeven & J.V. Swin- bition of fatty acid synthesis induces programmed cell
nen. 2005. RNA interference mediated silencing of the acetyl- death in human breast cancer cells. Cancer Res. 56: 2745–
CoA-carboxylase-alpha gene induces growth inhibition and 2747.
apoptosis of prostate cancer cells. Cancer Res. 65: 6719–6725. 26. Little, J.L., F.B. Wheeler, D.R. Fels, et al. 2007. Inhibition of
9. Smith, S. 1994. The animal fatty acid synthase: one gene, one fatty acid synthase induces endoplasmic reticulum stress in
polypeptide, seven enzymes. FASEB J. 8: 1248–1259. tumor cells. Cancer Res. 67: 1262–1269.
10. Little, J.L. & S.J. Kridel. 2008. Fatty acid synthase activity in 27. Fiorentino, M., G. Zadra, E. Palescandolo, et al. 2008. Over-
tumor cells. Subcell. Biochem. 49: 169–194. expression of fatty acid synthase is associated with palmitoy-
11. Kusakabe, T., M. Maeda, N. Hoshi, et al. 2000. Fatty acid lation of Wnt1 and cytoplasmic stabilization of beta-catenin
synthase is expressed mainly in adult hormone-sensitive cells in prostate cancer. Lab. Invest. 88: 1340–1348.
or cells with high lipid metabolism and in proliferating fetal 28. Kuhajda, F.P., E.S. Pizer, J.N. Li, et al. 2000. Synthesis and
cells. Histochem. Cytochem. 48: 613–622. antitumor activity of an inhibitor of fatty acid synthase. Proc.
12. López, M., C.J. Lelliott & A. Vidal-Puig. 2007. Hypotha- Natl. Acad. Sci. USA 97: 3450–3454.
lamic fatty acid metabolism: a housekeeping pathway that 29. Wortman, M.D., D.J. Clegg, D. D’Alessio, et al. 2003. C75
regulates food intake. Bioessays 29: 248–261. inhibits food intake by increasing CNS glucose metabolism.
13. Weiss, L., G.E. Hoffmann, R. Schreiber, et al. 1986. Fatty- Nat. Med. 9: 483–485.
acid biosynthesis in man, a pathway of minor importance: 30. Orita, H., J. Coulter, C. Lemmon, et al. 2007. Selective inhi-
purification, optimal assay conditions, and organ distribu- bition of fatty acid synthase for lung cancer treatment. Clin.
tion of fatty-acid synthase. Biol. Chem. Hoppe Seyler 367: Cancer Res. 13: 7139–7145.
905–912. 31. Orita, H., J. Coulter, E. Tully, et al. 2008. Inhibiting fatty acid
14. Porstmann, T., B. Griffiths, Y.L. Chung, et al. 2005. PKB/Akt synthase for chemoprevention of chemically induced lung
induces transcription of enzymes involved in cholesterol and tumors. Clin. Cancer Res. 14: 2458–2464.
fatty acid biosynthesis via activation of SREBP. Oncogene 24: 32. Kridel, S.J., F. Axelrod, N. Rozenkrantz & J.W. Smith. 2004.
6465–6481. Orlistat is a novel inhibitor of fatty acid synthase with anti-
15. Medes, G., A. Thomas & S. Weinhouse. 1953. Metabolism of tumor activity. Cancer Res. 64: 2070–2075.
neoplastic tissue IV: a study of lipid synthesis in neoplastic 33. Menendez, J.A., L. Vellon & R. Lupu. 2005. Orlistat:
tissue slices in vitro. Cancer Res. 13: 27–29. from antiobesity drug to anticancer agent in Her-2/neu

92 c 2010 The New York Academy of Sciences

Ann. N.Y. Acad. Sci. 1210 (2010) 86–93 
Oliveras et al. Fatty acid synthase and cancer

(erbB-2)-overexpressing gastrointestinal tumors? Exp. Biol. fects of epigallocatechin gallate (EGCG) and C75. Breast
Med. 230: 151–154. Cancer Res. Treat. 109: 471–479.
34. Browne, C.D., E.J. Hindmarsh & J.W. Smith. 2006. Inhibition 38. Puig, T., J. Relat, P.F. Marrero, et al. 2008. Green tea catechin
of endothelial cell proliferation and angiogenesis by orlistat, inhibits fatty acid synthase without stimulating carnitine
a fatty acid synthase inhibitor. FASEB J. 20: 2027–2035. palmitoyltransferase-1 or inducing weight loss in experi-
35. Lin, J.K. & S.Y. Lin-Shiau. 2006. Mechanisms of hypolipi- mental animals. Anticancer Res. 28: 3671–3676.
demic and anti-obesity effects of tea and tea polyphenols. 39. Colomer, R., T. Puig, J. Brunet, et al. 2007. Novel polyhydrox-
Mol. Nutr. Food Res. 50: 211–217. ylated compounds as fatty acid synthase (FASN) inhibitors.
36. Jatoi, A., N. Ellison, P.A. Burch, et al. 2003. A phase II trial European Patent EP07110956.5.
of green tea in the treatment of patients with androgen 40. Puig, T., C. Turrado, B. Benhamú, et al. 2009. Novel In-
independent metastatic prostate carcinoma. Cancer 97: hibitors of Fatty Acid Synthase with Anticancer Activity.
1442–1446. Clin Cancer Res. 15: 7608–7615.
37. Puig, T., A. Vázquez-Martı́n, J. Relat, et al. 2008. Fatty acid 41. Relat, J. & T. Puig. 2010. Frontiers in Drug Design and
metabolism in breast cancer cells: differential inhibitory ef- Discovery. 5: 211–235.

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