N-Alkylated
polyamine analogues have been shown to exert antiproliferative effects in several
tumor models, with the bis-ethyl derivatives exerting the greatest suppression of
polyamines by virtue of down-regulation of the
polyamine biosynthetic
enzymes. Pancreatic
adenocarcinoma presents a challenge both clinically and experimentally due to its inherent resistance to conventional
therapy, which results in its having the worst 5-year survival rate of all
cancers. We have previously shown that N1,N12-bis(ethyl)spermine (
BESPM) is much more potent than the
polyamine enzyme inhibitor alpha-difluoromethylornithine (DFMO) against pancreatic
adenocarcinoma cell lines. In the present study, we compared the biochemical and antiproliferative effects of two N-alkylated
polyamine analogues, N1,N14-bis(ethyl)homospermine (
BEHSPM) and
N1,N11-bis(ethyl)norspermine (
BENSPM) in two human pancreatic ductal
adenocarcinoma cell lines, PANC-1 (poorly differentiated) and BxPC-3 (moderately well-differentiated), and in the WD PaCa (well-differentiated ductal) hamster cell line.
BENSPM displayed greater antiproliferative activity in the human
pancreatic cancer cell lines, whereas
BEHSPM was more potent in the hamster cell line. Both
BEHSPM and
BENSPM suppress the activity of the major biosynthetic
enzymes ornithine decarboxylase and
S-adenosylmethionine decarboxylase. However, the induction of
polyamine depletion in the human cell lines was only modest for
BENSPM and minimal for
BEHSPM, which suggests that the substantial antiproliferative activity of these analogues may result from mechanisms other than
polyamine depletion. The somewhat greater
polyamine depletion seen following treatment with
BENSPM is thought to result from its striking induction of
spermidine/
spermine N1-acetyltransferase. The biochemical and antiproliferative activity of
BENSPM makes it an attractive agent for further preclinical and clinical development, especially in
pancreatic cancer.