Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer.
One of the key limiting factors in the treatment of advanced stage human epithelial malignancies is the lack of selective molecular targets for antineoplastic therapy. A substantial subset of human ovarian, endometrial, breast, colorectal, and prostatic cancers exhibit increased endogenous fatty acid biosynthesis and overexpress certain enzymes in the pathway. Cell lines derived from these tumors use endogenously synthesized fatty acids for cellular functions, whereas normal cells and tissues appear to utilize dietary lipids preferentially. We have previously shown that the difference in fatty acid biosynthesis between cancer and normal cells is an exploitable target for metabolic inhibitors in vitro. Here, we report observations in vivo using the i.p. model of the multiply drug-resistant OVCAR-3 human ovarian carcinoma in nude mice which demonstrate that: (a) fatty acid synthase overexpression in OVCAR-3 is comparable to levels in primary human tumors assessed by immunohistochemistry; (b) fatty acid synthetic activity of OVCAR-3 is comparably elevated in vitro and in vivo and is 4 to >20-fold higher than normal murine tissues; (c) treatment with the specific fatty acid synthase inhibitor, cerulenin, markedly reduces tumor cell fatty acid biosynthesis in vivo; (d) fatty acid synthase inhibition produces regression of established ascites tumor; and (e) treatment with cerulenin causes reduction in ascites incidence, delay in onset of ascites, and significantly increased survival (P<0.04).
Pizer
E S
ES
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Wood
F D
FD
Heine
H S
HS
Romantsev
F E
FE
Pasternack
G R
GR
Kuhajda
F P
FP
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D001201:Ascites / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D002569:Cerulenin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D018450:Disease Progression; D018432:Drug Resistance, Multiple; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D005227:Fatty Acids; D002569:Cerulenin; D064429:Fatty Acid Synthases