De novo production of
phosphatidic acid (PA) in
tumor cells is required for
phospholipid biosynthesis and growth of
tumor cells. In addition, PA production by
phospholipase D has been cited among the effects of certain oncogenes and
growth factors. In this report, it has been demonstrated that enhanced
phospholipid metabolism through PA in
tumor cells can be exploited pharmacologically for development of
anticancer agents, such as
CT-2584, a
cancer chemotherapeutic
drug candidate currently in Phase II clinical trials. By inhibiting
CTP:
choline-phosphate cytidylyltransferase (CT),
CT-2584 caused de novo
phospholipid biosynthesis via PA to be shunted away from
phosphatidylcholine (PC) and into
phosphatidylinositol (PI), the latter of which was doubled in a variety of CT-2584-treated tumor cell lines. In contrast, cytotoxic concentrations of
cisplatin did not induce accumulation of PI, indicating that PI elevation by
CT-2584 was not a general consequence of
chemotherapy-induced cell death. Consistent with this mechanism of action,
propranolol, an inhibitor of PA
phosphohydrolase and
phosphatidylcholine biosynthesis, was also cytotoxic to tumor cell lines, induced PI accumulation, and potentiated the activity of
CT-2584 in cytotoxicity assays. As expected from biophysical properties of anionic
phospholipids on cellular membranes,
CT-2584 cytotoxicity was associated with disruption and swelling of endoplasmic reticulum and mitochondria. We conclude that
CT-2584 effects a novel mechanism of cytotoxicity to
cancer cells, involving a specific modulation of
phospholipid metabolism.