Influence of coenzyme A-independent transacylase and cyclooxygenase inhibitors on the proliferation of breast cancer cells

Recent studies have demonstrated that arachidonic acid (AA) may serve as an important signal that blocks cell proliferation of certain neoplastic cell s. The current study was conducted to determine whether disruption of AA ho meostasis influences breast cancer cell proliferation and death. Initial ex periments revealed that inhibition of AA remodeling through membrane phosph olipids by inhibitors of the enzyme, coenzyme A-independent transacylase (C oA-IT), attenuates the proliferation of the estrogen receptor-negative, MDA -MB-231, and estrogen receptor-positive, MCF-7 breast cancer cell lines. Th is growth inhibition was accompanied by a marked accumulation of AA in both free fatty acid and triglyceride forms, a marker of intracellular AA stres s within mammalian cells. Cell cycle synchronization experiments revealed t hat the CoA-IT inhibitor, SB-98625, blocked MDA-MB-231 cell replication in early to mid G(1) phase. Time-lapse video microscopy, used to observe the c hanges in cell morphology associated with apoptosis, indicated that SE-9862 5 treatment induced early rounding and occasional blebbing but not Late apo ptotic events, blistering, and lysis. The cyclooxygenase inhibitors, NS-398 and indomethacin, were found to be less potent blockers of cell proliferat ion and poor inducers of cellular AA accumulation than CoA-IT inhibitors in these breast cancer cell lines. Finally, AA provided exogenously blocked t he proliferation of MCF-7 cells, and this effect could be attenuated in MCF -7 cells overexpressing the glutathione peroxidase gene, GSHPx-1. Taken tog ether, these experiments suggest that disruption of AA remodeling in a mann er that increases intracellular AA may represent a novel therapeutic strate gy to reduce cancer cell proliferation and that an oxidized AA metabolite i s likely to mediate this effect.