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Increased breast cancer cell toxicity by palladination of the polyamine analogue N-1,N-11-bis(ethyl)norspermine

Silva, Tania M.; Fiuza, Sonia M.; Marques, Maria P. M.; Persson, Lo LU and Oredsson, Stina (2014) In Amino Acids 46(2). p.339-352
Abstract
Breast cancer is one of the most common malignant tumor forms among women and many women succumb to their disease. Thus, new anticancer agents that can efficiently improve patient survival are of the utmost importance. In this study, the effects of the polyamine analogues N (1),N (11)-bis(ethyl)norspermine (BENSpm) and N (1)-cyclo-propylmethyl-N (11)-ethylnorspermine (CPENSpm) and the synthesized dinuclear complexes Pd(2)BENSpm (Pd-BENSpm), Pt(2)CPENSpm (Pt-CPENSpm) and Pd(2)Spm (Pd-Spm) were investigated in normal-like breast epithelial MCF-10A cells and the breast cancer cell lines JIMT-1 and L56BR-C1. The overall data show that palladination of BENSpm resulted in enhanced cytotoxicity, in contrast to platination of CPENSpm that reduced... (More)
Breast cancer is one of the most common malignant tumor forms among women and many women succumb to their disease. Thus, new anticancer agents that can efficiently improve patient survival are of the utmost importance. In this study, the effects of the polyamine analogues N (1),N (11)-bis(ethyl)norspermine (BENSpm) and N (1)-cyclo-propylmethyl-N (11)-ethylnorspermine (CPENSpm) and the synthesized dinuclear complexes Pd(2)BENSpm (Pd-BENSpm), Pt(2)CPENSpm (Pt-CPENSpm) and Pd(2)Spm (Pd-Spm) were investigated in normal-like breast epithelial MCF-10A cells and the breast cancer cell lines JIMT-1 and L56BR-C1. The overall data show that palladination of BENSpm resulted in enhanced cytotoxicity, in contrast to platination of CPENSpm that reduced cytotoxicity, which might be explained by differences in the cellular uptake of Pd-BENSpm and Pt-CPENSpm. BENSpm and Pd-BENSpm treatment reduced the CD44(+)CD24(-) putative cancer stem cell population, evaluated by flow cytometry. Furthermore, Pd-BENSpm was the most efficient compound regarding induction of DNA damage and decrease in colony formation in soft agar. Pt-CPENSpm and Pd-Spm, on the other hand, were shown to be the least toxic compounds of all tested. Pd-Spm efficiently reduced the cellular glutathione levels, which probably was a consequence of its metabolic inactivation by conjugation to this endogenous thiol. The normal-like cells were found to be less sensitive to the agents than the breast cancer cells. Our findings show that Pd-BENSpm exhibits promising anticancer effects which render it suitable for further optimization to develop a new metal-based chemotherapeutic drug for breast cancer treatment. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Polyamine analogues, Palladium (Pd)(II) complexes, Platinum (Pt)(II) complexes, DNA damage, Cancer stem cells
in
Amino Acids
volume
46
issue
2
pages
339 - 352
publisher
Springer
external identifiers
  • wos:000330957300010
  • scopus:84895910981
ISSN
0939-4451
DOI
10.1007/s00726-013-1621-y
language
English
LU publication?
yes
id
2475d580-4f1e-4a89-a0c3-f9cf5a4178f5 (old id 4376358)
date added to LUP
2014-04-07 09:19:20
date last changed
2017-11-12 03:07:48
@article{2475d580-4f1e-4a89-a0c3-f9cf5a4178f5,
  abstract     = {Breast cancer is one of the most common malignant tumor forms among women and many women succumb to their disease. Thus, new anticancer agents that can efficiently improve patient survival are of the utmost importance. In this study, the effects of the polyamine analogues N (1),N (11)-bis(ethyl)norspermine (BENSpm) and N (1)-cyclo-propylmethyl-N (11)-ethylnorspermine (CPENSpm) and the synthesized dinuclear complexes Pd(2)BENSpm (Pd-BENSpm), Pt(2)CPENSpm (Pt-CPENSpm) and Pd(2)Spm (Pd-Spm) were investigated in normal-like breast epithelial MCF-10A cells and the breast cancer cell lines JIMT-1 and L56BR-C1. The overall data show that palladination of BENSpm resulted in enhanced cytotoxicity, in contrast to platination of CPENSpm that reduced cytotoxicity, which might be explained by differences in the cellular uptake of Pd-BENSpm and Pt-CPENSpm. BENSpm and Pd-BENSpm treatment reduced the CD44(+)CD24(-) putative cancer stem cell population, evaluated by flow cytometry. Furthermore, Pd-BENSpm was the most efficient compound regarding induction of DNA damage and decrease in colony formation in soft agar. Pt-CPENSpm and Pd-Spm, on the other hand, were shown to be the least toxic compounds of all tested. Pd-Spm efficiently reduced the cellular glutathione levels, which probably was a consequence of its metabolic inactivation by conjugation to this endogenous thiol. The normal-like cells were found to be less sensitive to the agents than the breast cancer cells. Our findings show that Pd-BENSpm exhibits promising anticancer effects which render it suitable for further optimization to develop a new metal-based chemotherapeutic drug for breast cancer treatment.},
  author       = {Silva, Tania M. and Fiuza, Sonia M. and Marques, Maria P. M. and Persson, Lo and Oredsson, Stina},
  issn         = {0939-4451},
  keyword      = {Breast cancer,Polyamine analogues,Palladium (Pd)(II) complexes,Platinum (Pt)(II) complexes,DNA damage,Cancer stem cells},
  language     = {eng},
  number       = {2},
  pages        = {339--352},
  publisher    = {Springer},
  series       = {Amino Acids},
  title        = {Increased breast cancer cell toxicity by palladination of the polyamine analogue N-1,N-11-bis(ethyl)norspermine},
  url          = {http://dx.doi.org/10.1007/s00726-013-1621-y},
  volume       = {46},
  year         = {2014},
}