Effects of the polyamine analogues N-1-Ethyl-N-11-((cyclopropyl)methyl)-4,8-diazaundecane and N-1-ethyl-N-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 p olyamine metabolism may be an effective way to stop the growth of prostate cancer cells. The unsymmetrically alkylated polyamine analogues N-1-ethyl-N -11-((cyclopropyl)methyl)-4,8-diazaundecane (CPENSpm) and N-1-ethyl-N-11-(( cycloheptyl)methyl)-4,8-diazaundecane (CHENSpm) have been shown previously to have cytotoxic effects in breast and non-small cell lung cancer cells. W e have now investigated the responses of three human prostate cancer cell l ines, LNCaP, PC3, and Du145, to these polyamine analogues and to the symmet rically alkylated analogue N-1,N-11-bis(ethyl)norspermine (BE 3-3-3), The D u145 cell line, in which IC,, values ranged from 0.65 to 0.8 mu M, was the most sensitive to each of the polyamine analogues, although significant gro wth inhibition resulted in the other cell lines as well. CPENSpm and BE 3-3 -3 but not CHENSpm caused significant decreases in the intracellular spermi ne and spermidine pools, although all three analogues accumulated to high l evels in each of the cell lines. Spermidine/spermine N-1-acetyltransferase activity was induced 23-250-fold in response to CPENSpm and BE 3-3-3, but i t was not affected by CHENSpm, None of the analogues bad significant effect s on the activities of ornithine decarboxylase or S-adenosylmethionine deca rboxylase. 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 onl y in LNCaP cells, The ability to induce PCD was the only parameter measured that correlated with cell line sensitivity to these polyamine analogues.