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Published on: July 8, 2020
Concentration-dependent effects of N1, N11-diethylnorspermine on melanoma cell proliferation
Rodney F Minchin1, Samuel Knight, Ajanthy Arulpragasam
1School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia. r.minchin@uq.edu.au
Abstract:
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.
Insights
N1, N11-diethylnorspermine (DENSPM), an anticancer drug, paradoxically increased proliferation in resistant melanoma cells at low doses by mimicking natural polyamines. Higher doses inhibited growth across various cancers.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- N1, N11-diethylnorspermine (DENSPM) is a polyamine analog investigated as an anticancer agent.
- Preclinical studies show promising activity, but responsiveness varies significantly across human cancers.
Purpose of the Study:
- To investigate the causes of variable responsiveness to DENSPM in human cancers.
- To understand the mechanism of DENSPM action, particularly at low concentrations in resistant melanoma cells.
Main Methods:
- Assessed cell proliferation and growth inhibition of human melanoma cells at varying DENSPM concentrations.
- Investigated DENSPM's effect on polyamine transport and its ability to rescue cells from polyamine depletion.
- Determined IC50 values for growth inhibition across different cell lines.
Main Results:
- Low DENSPM concentrations (<10 microM) increased proliferation in drug-resistant melanoma cells.
- Higher DENSPM concentrations caused growth inhibition with IC50 values ranging from 2-180 microM.
- DENSPM downregulated polyamine transport and rescued cells from ornithine decarboxylase inhibitor-induced growth arrest.
Conclusions:
- DENSPM may mimic endogenous polyamines at low, clinically relevant concentrations, promoting proliferation in resistant melanoma.
- Understanding DENSPM's dual action is crucial for optimizing its therapeutic application in cancer treatment.
