Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells.
One of the key limiting factors in the treatment of advanced stage human epithelial malignancies is the lack of new, selective molecular targets for antineoplastic therapy. A substantial subset of human breast, ovarian, endometrial, colorectal, and prostatic cancers express elevated levels of fatty acid synthase, the major enzyme required for endogenous fatty acid biosynthesis, and carcinoma lines are growth inhibited by cerulenin, a noncompetitive inhibitor of fatty acid synthase. We have shown previously that the difference in fatty acid biosynthesis between cancer and normal cells is an exploitable target for metabolic inhibitors in the in vitro setting and in vivo in a human ovarian carcinoma xenograft in nude mice. Here, we report that cerulenin treatment of human breast cancer cells inhibits fatty acid synthesis within 6 h after exposure, that loss of clonogenic capacity occurs within the same interval, and that DNA fragmentation and morphological changes characteristic of apoptosis ensue.
Pizer
E S
ES
Division of Molecular Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Jackisch
C
C
Wood
F D
FD
Pasternack
G R
GR
Davidson
N E
NE
Kuhajda
F P
FP
D000935:Antifungal Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002569:Cerulenin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000032:analysis*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D004273:DNA, Neoplasm; D005227:Fatty Acids; D002569:Cerulenin; D064429:Fatty Acid Synthases