Intracellular accumulation and cytotoxic effect of (8-thiotheophyllinate) (triphenylphosphine) gold(I) in Friend leukemia cells.
Following continuous exposure to tTAuP in medium containing 10% fetal calf serum (FCS), cells resistant to doxorubicin (DOX-RFLC) were 3 fold more resistant to tTAuP than its sensitive counterpart (FLC). Moreover, FLC were 100 fold more sensitive to tTAuP when the cells were grown in the absence of FCS but in the presence of synthetic medium (BMS). When the cytotoxic effect was measured after short-term exposure (60 min) followed by 72 hr incubation in drug-free medium, unexpectedly, DOX-RFLC were 8 fold more sensitive [ID50 = 1.5 microM] than FLC [ID50 = 12 microM] to tTAuP. When FLC were exposed 60 min at different temperatures (4, 25 or 37 degrees C) to tTAuP prior to 72 hr incubation in drug free medium, the ID50 was achieved at 20, 13 and 3 microM respectively). In contrast, when DOX-RFLC were treated in similar conditions, the cytotoxic activity of tTAuP did not vary following exposure at 4, 25 or 37 degrees C. Although the mechanism of action of gold compounds is still unknown we have assumed that tTAuP cytotoxicity is related to the ease with which it is accumulated. This assumption was supported by the analysis of tTAuP incorporation by SXRF. The results reported here show that tTAuP accumulates rapidly in the cell and is distributed in the cytoplasmic and the nuclear fractions. It is suggested that accumulation is mediated by passive diffusion. However, the detection of gold binding to DNA in complexes resistant to solvent treatments suggests that interaction with macromolecules can be mediated by the formation of covalently bound complexes.
Arizti
M P
MP
Dpto. de Biología Celular, Facultad de Medicina, Universidad del País Vasco, Vizcaya, Spain.
Garcia-Orad
A
A
Sommer
F
F
Silvestro
L
L
Massiot
P
P
Chevallier
P
P
Gutiérrez-Zorrilla
J M
JM
Colacio
E
E
Martinez de Pancorbo
M
M
Tapiero
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001692:Biological Transport; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D004273:DNA, Neoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D007700:Kinetics; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000378:metabolism* / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D003470:Culture Media; D004273:DNA, Neoplasm; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C069630:8-thiotheophyllinate-triphenylphosphine gold(I); D004317:Doxorubicin; D013806:Theophylline