Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines

De novo production of phosphatidic acid (PA) in tumor cells is required for phospholipid biosynthesis and growth of tumor cells. In addition, PA produ ction by phospholipase D has been cited among the effects of certain oncoge nes and growth factors. In this report, it has been demonstrated that enhan ced phospholipid metabolism through PA in tumor cells can be exploited phar macologically for development of anticancer agents, such as CT-2584, a canc er chemotherapeutic drug candidate currently in Phase II clinical trials. B y inhibiting CTP:choline-phosphate cytidylyltransferase (CT), CT-2584 cause d de novo phospholipid biosynthesis via PA to be shunted away from phosphat idylcholine (PC) and into phosphatidylinositol (PI), the latter of which wa s doubled in a variety of CT-2584-treated tumor cell lines. In contrast, cy totoxic concentrations of cisplatin did not induce accumulation of PI, indi cating that PI elevation by CT-2584 was not a general consequence of chemot herapy-induced cell death. Consistent with this mechanism of action, propra nolol, an inhibitor of PA phosphohydrolase and phosphatidylcholine biosynth esis, was also cytotoxic to tumor cell lines, induced PI accumulation, and potentiated the activity of CT-2584 in cytotoxicity assays. As expected fro m biophysical properties of anionic phospholipids on cellular membranes, CT -2584 cytotoxicity was associated with disruption and swelling of endoplasm ic reticulum and mitochondria. We conclude that CT-2584 effects a novel mec hanism of cytotoxicity to cancer cells, involving a specific modulation of phospholipid metabolism.