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Concentration‐dependent effects of N 1 , N 11 ‐diethylnorspermine on melanoma cell proliferation
Author(s) -
Minchin Rodney F.,
Knight Samuel,
Arulpragasam Ajanthy,
FogelPetrovic Mirjana
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21359
Subject(s) - polyamine , spermidine , ornithine decarboxylase , cell growth , biology , intracellular , endogeny , cell culture , endocrinology , microbiology and biotechnology , medicine , cancer research , biochemistry , enzyme , genetics
N 1 , N 11 ‐Diethylnorspermine (DENSPM) is a polyamine analog that is currently under investigation as a novel anticancer drug. Although it has shown promising preclinical activity, there has been large variation in responsiveness reported between different human cancers. During our studies into the causes of this variation, we observed a consistent increase in cell proliferation at low drug concentrations (<10 μM) in human melanoma cells resistant to the drug. At higher concentrations, growth inhibition was seen in all cell lines, with IC 50 values ranging 2–180 μM. We hypothesized that DENSPM may mimic endogenous polyamines at low concentrations, supporting cell growth in resistant lines. We also observed that DENSPM downregulated polyamine transport in a manner similar to that for spermidine, a finding that confirms previous reports. Finally, DENSPM could rescue cells from growth arrest by the ornithine decarboxylase inhibitor difluoromethylornithine, which depletes intracellular polyamines. Taken together, these results suggest that DENSPM, at clinically relevant concentrations, can mimic endogenous polyamines and induce proliferation in resistant human melanoma cells. © 2005 Wiley‐Liss, Inc.