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.