1H and 31P NMR and HPLC studies of mouse L1210 leukemia cell extracts: the effect of Au(I) and Cu(I) diphosphine complexes on the cell metabolism.
The effect of the antitumor complex [Au(dppe)2]Cl (where dppe is Ph2P(CH2)2PPh2) on the overall metabolism of cultured mouse L1210 leukemia cells was investigated by comparing 1H and 31P NMR spectra of perchloric acid extracts of cells incubated for 1 h in the presence and absence of 2 microM [Au(dppe)2]Cl. There were marked (ca. two-fold) increases in the levels of lactate and almost all detectable amino acids suggesting a drug-induced increase in the rate of glycolysis and inhibition of protein synthesis. The levels of taurine and phosphorylcholine were significantly decreased and 31P NMR spectra revealed a depletion of nucleoside triphosphates (NTP). The effect on nucleotide metabolism was investigated further by separating purine and pyrimidine nucleotides and precursors by anion-exchange HPLC. NTP levels were depleted by ca. 70-90% and there was a ca. three- to four-fold increase in nucleoside di- and monophosphates. The effect is postulated to be the result of uncoupling of mitochondrial oxidative phosphorylation. The Cu(I) complex [Cu(Ph2PCH = CHPPh2)2]Cl produced a similar effect on the cellular metabolism but was more potent. The water-soluble complex [Cu(Ph2P(CH2)PEt2)2]Cl caused the accumulation of cellular amino acids at a concentration that did not significantly deplete ATP levels.
Berners-Price
S J
SJ
Department of Biochemistry, University of Sydney, New South Wales, Australia.
Sant
M E
ME
Christopherson
R I
RI
Kuchel
P W
PW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000494:pharmacology*; D006046:Gold / Q000494:pharmacology*; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C069604:bis-(1,2-bis(diphenylphosphino)ethene)Cu(I); C069605:bis(1,2-bis-(diphenylphosphino)ethane)Cu(I); C050185:bis(1,2-bis(diphenylphosphino)ethane)gold(I); D006046:Gold; D003300:Copper