Difluoromethylornithine and ethylglyoxal bis(guanylhydrazone) as inhibitors of human renal carcinoma cell proliferation and polyamine metabolism.
The significance of the polyamines putrescine, spermidine and spermine for the neoplastic proliferation of the human renal carcinoma cell line ACHN was investigated. For this purpose cells were cultured in vitro for 4 days with or without the addition of pathway inhibitors of polyamine biosynthetic enzymes. It was found that treatment of ACHN cells with the specific ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) resulted in profound decreases of ODC activity, polyamine content and cell proliferation rates along with a compensatory increase in S-adenosylmethionine decarboxylase (SAMDC) activity. Ethylglyoxal bis(guanylhydrazone) (EGBG), a SAMDC inhibitor, evoked a similar reduction of cell proliferation and contents of spermidine and spermine. EGBG also seemed to stabilize SAMDC, as evidenced by a highly enhanced SAMDC activity during enzyme assays in the absence of the inhibitor. Furthermore, EGBG treatment caused on activation of ODC and a subsequent build-up of putrescine. The impact on polyamine contents and proliferation rates were synergistic when the inhibitors were used in combination. None of the inhibitors alone exerted a cytocidal activity. It is concluded that polyamines may be implicated in the regulation of the neoplastic proliferation of cultured human renal carcinoma cells and that polyamine synthesis inhibitors may prove valuable in clinical treatment of this disease.
Sjöholm
A
A
Department of Endocrinology, Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Larsson
R
R
Nygren
P
P
D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008935:Mitoguazone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000633:toxicity
D004273:DNA, Neoplasm; D011073:Polyamines; C041127:ethylglyoxal bis(guanylhydrazone); D013096:Spermine; D014750:Vincristine; D014700:Verapamil; D009955:Ornithine Decarboxylase; D008935:Mitoguazone; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine