Concentration-dependent effects of N1, N11-diethylnorspermine on melanoma cell proliferation.
N1, N11-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 microM) in human melanoma cells resistant to the drug. At higher concentrations, growth inhibition was seen in all cell lines, with IC50 values ranging 2-180 microM. 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.
Minchin
Rodney F
RF
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia. r.minchin@uq.edu.au
Knight
Samuel
S
Arulpragasam
Ajanthy
A
Fogel-Petrovic
Mirjana
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D012878:Skin Neoplasms / Q000473:pathology*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine; D009955:Ornithine Decarboxylase