Selective inhibition of fatty acid synthase for lung cancer treatment.
OBJECTIVE
Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. However, in vitro use of previous generations of FAS inhibitors has been limited by severe, but reversible, anorexia in treated animals, which is thought to be related to a parallel stimulation of fatty acid oxidation by these agents. This study investigated pharmacologic inhibition of FAS using C93, a rationally designed molecule that inhibits FAS activity without affecting fatty acid oxidation in preclinical models of lung cancer.


METHODS
Activity of C93 on FAS and fatty acid oxidation was evaluated in cultured non-small cell lung cancer (NSCLC) cells. Antineoplastic activity of the compound, given orally or by i.p. injection, was evaluated in s.c. and orthotopic NSCLC xenografts.


RESULTS
Our experiments confirm that C93 effectively inhibits FAS without stimulating fatty acid oxidation in lung cancer cells. More importantly, C93 significantly inhibits the growth of both s.c. and orthotopic xenograft tumors from human NSCLC cell lines without causing anorexia and weight loss in the treated animals.


CONCLUSIONS
We conclude that inhibition of FAS can be achieved without parallel stimulation of fatty acid oxidation and that inhibition of tumor growth in vivo can be achieved without anorexia and weight loss. Thus, this therapeutic strategy holds promise for clinical treatment of cancers, including non-small cell lung cancer, the leading cause of cancer mortality in the United States and Europe.
Orita
Hajime
H
Department of Pathology and Johns Hopkins Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Coulter
Jonathan
J
Lemmon
Colleen
C
Tully
Ellen
E
Vadlamudi
Aravinda
A
Medghalchi
Susan M
SM
Kuhajda
Francis P
FP
Gabrielson
Edward
E
D000284:Administration, Oral; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D054872:Fatty Acid Synthesis Inhibitors; D005227:Fatty Acids; D064429:Fatty Acid Synthases