Effects of the polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane and N1-ethylN-11-((cycloheptyl)methyl)-4,8-diazaundecane in human prostate cancer cells.
The high levels of polyamines maintained in the prostate suggest that these compounds are important to prostate cell function and that disruption of polyamine metabolism may be an effective way to stop the growth of prostate cancer cells. The unsymmetrically alkylated polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaunde-cane (CPENSpm) and N1-ethyl-N11-((cycloheptyl)methyl)-4,8-diazaundecane (CHENSpm) have been shown previously to have cytotoxic effects in breast and non-small cell lung cancer cells. We have now investigated the responses of three human prostate cancer cell lines, LNCaP, PC3, and Du145, to these polyamine analogues and to the symmetrically alkylated analogue N1,N11-bis(ethyl)norspermine (BE 3-3-3). The Du145 cell line, in which IC50 values ranged from 0.65 to 0.8 microM, was the most sensitive to each of the polyamine analogues, although significant growth inhibition resulted in the other cell lines as well. CPENSpm and BE 3-3-3 but not CHENSpm caused significant decreases in the intracellular spermine and spermidine pools, although all three analogues accumulated to high levels in each of the cell lines. Spermidine/spermine N1-acetyltransferase activity was induced 23-250-fold in response to CPENSpm and BE 3-3-3, but it was not affected by CHENSpm. None of the analogues had significant effects on the activities of ornithine decarboxylase or S-adenosylmethionine decarboxylase. Quantitation of DNA fragmentation indicative of programmed cell death (PCD) showed that both CPENSpm and CHENSpm were effective inducers of PCD in all three prostate cell lines. In contrast, BE 3-3-3 led to PCD only in LNCaP cells. The ability to induce PCD was the only parameter measured that correlated with cell line sensitivity to these polyamine analogues.
McCloskey
D E
DE
Pennsylvania State University College of Medicine, Hershey, USA.
Woster
P M
PM
Casero
R A
RA
Davidson
N E
NE
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation; D006801:Humans; D007700:Kinetics; D008297:Male; D011073:Polyamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D011437:Propylamines / Q000493:pharmacokinetics / Q000633:toxicity; D011471:Prostatic Neoplasms; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C118771:N(1)-ethyl-N-(11)-((cycloheptyl)methyl)-4,8-diazaundecane; D011073:Polyamines; D011437:Propylamines; C059685:N(1),N(11)-diethylnorspermine; C083629:N(1)-ethyl-N-(11)-((cyclopropyl)methyl)-4,8-diazaundecane-1,11-diamine; D013096:Spermine; D013095:Spermidine; D011700:Putrescine