title: Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines.
abstract: 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.
authors.affiliation: Cell Therapeutics. inc., Seattle, Washington 98119, USA. rfinney@ctiseattle.com
authors.forename: R E
authors.initials: RE
authors.lastname: Finney
authors.forename: E
authors.initials: E
authors.lastname: Nudelman
authors.forename: T
authors.initials: T
authors.lastname: White
authors.forename: S
authors.initials: S
authors.lastname: Bursten
authors.forename: P
authors.initials: P
authors.lastname: Klein
authors.forename: L L
authors.initials: LL
authors.lastname: Leer
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Waggoner
authors.forename: J W
authors.initials: JW
authors.lastname: Singer
authors.forename: R A
authors.initials: RA
authors.lastname: Lewis
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002797:Choline Kinase; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D003567:Cytidine Diphosphate Diglycerides / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010712:Phosphatidic Acids / Q000096:biosynthesis / Q000378:metabolism; D010713:Phosphatidylcholines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010716:Phosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000633:toxicity*
chemical_list: D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D003567:Cytidine Diphosphate Diglycerides; D010712:Phosphatidic Acids; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D014970:Xanthines; C106011:CT 2584; D011433:Propranolol; D002797:Choline Kinase; D019916:Choline-Phosphate Cytidylyltransferase