title: 1H NMR visible lipids are induced by phosphonium salts and 5-fluorouracil in human breast cancer cells.
abstract: Cationic lipophilic phosphonium salts (CLPS) selectively accumulate in the mitochondria of neoplastic cells and inhibit mitochondrial function. The effects of the CLPS p-(triphenylphosphoniummethyl) benzaldehyde chloride (drug A), and [4-(hydrazinocarboxy)-1-butyl] tris-(4-dimethylaminophenyl) phosphonium chloride (drug B), on human breast cells of differing biological properties were assessed using growth inhibition assays and 1H NMR. Drug A and, to a lesser extent, drug B demonstrated selective growth inhibition of the highly tumorigenic DU4475 breast carcinoma cell line compared to the transformed HBL-100 human breast cell line. However, in contrast to previous studies using other cell lines, no synergistic activity was found when the drugs were used in combination. 1H NMR demonstrated significant increases in mobile lipid acyl chain resonances in both cell lines treated with cytotoxic doses (IC50, 48 h) of the drugs used either alone or in combination. Two-dimensional NMR revealed accompanying decreases in phosphocholine/Lys levels in HBL-100 cells treated with A, B, or a 1:1 combination A+B at the IC50, and in DU4475 cells treated with drug A (IC50). This was accompanied by significant increases in cho/Lys ratios with IC50 A or combination A+B treatment. Similar spectra were observed in cells treated with 5-fluorouracil but not methotrexate, indicating that mobile lipid accumulation is a general but not universal response to cytotoxic insult.
authors.affiliation: Department of Cancer Medicine, University of Sydney, Sydney, Australia.
authors.forename: W A
authors.initials: WA
authors.lastname: Cooper
authors.forename: W A
authors.initials: WA
authors.lastname: Bartier
authors.forename: D C
authors.initials: DC
authors.lastname: Rideout
authors.forename: E J
authors.initials: EJ
authors.lastname: Delikatny
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; C113117:tributylmethyl phosphonium chloride; D005472:Fluorouracil; D008727:Methotrexate