Ironjustic
Sat, Nov-03-07, 06:15
"Mediated through the chelation of intracellular iron"
Antiproliferative and apoptotic effects in rat and human
hepatoma cell cultures of the orally active iron chelator
ICL670 compared to CP20: a possible relationship with
polyamine metabolism Authors: Lescoat, G.1;
Chantrel-Groussard, K.1; Pasdeloup, N.1; Nick, H=2E2; Brissot,
P.1; Gaboriau, F.1
Source: Cell Proliferation, Volume 40, Number 5, October 2007
, pp. 755-767(13)
Publisher: Blackwell Publishing
Abstract:
Objective:=E2=80=82Iron loading has been observed to have a
hyperproliferat= ive effect on hepatocytes in vitro and on
tumour cells in vivo; removal of this iron being required to
induce antitumour activity. Material and
Methods:=E2=80=82Antiproliferative effects of orally active
tridentate iron chelator ICL670 (deferasirox) and bidentate
iron chelator CP20 (deferiprone), mediated through the
chelation of intracellular iron, were compared in rat hepatoma
cell line FAO and human hepatoma cell line HUH7.
Results:=E2=80=82In FAO cell cultures, we have shown that
ICL670 decreased cell viability and DNA replication and
induced apoptosis more efficiently than an iron-binding
equivalent concentration of
CP20. Moreover, ICL670 decreased significantly the number of
the cells in G2-M phase. In the HUH7 cell cultures,
ICL670 and a four-time higher iron-binding equivalent
concentration of CP20, decreased cell viability and DNA
replication in the same range. CP20 increased the number
of the cells in G2-M phase. However, ICL670 inhibited
polyamine biosynthesis by decreasing ornithine
decarboxylase mRNA level; in contrast, CP20 increased
polyamine biosynthesis, particularly putrescine level,
by stimulating spermidine-spermine N1-acetyl transferase
activity that could activate the polyamine retro-
conversion pathway. By mass spectrometry, we observed
that ICL670 cellular uptake was six times higher than
CP20. Conclusions:=E2=80=82These results suggest that
ICL670 has a powerful antitumoural effect and blocks
cell proliferation in neoplastic cells by a pathway
different from that of CP20 and may constitute a
potential adjuvant drug for anticancer therapy. Document
Type: Research article
DOI: 10.1111/j.1365-2184.2007.00468.x
Affiliations: 1: Inserm, U522, Rennes, F-35000 France; Univ
Rennes 1, Rennes, F-35000 France; IFR 140, Rennes, F-35000
France, 2: Novartis Institutes for BioMedical Research, Basel
4002, Switzerland
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
Antiproliferative and apoptotic effects in rat and human
hepatoma cell cultures of the orally active iron chelator
ICL670 compared to CP20: a possible relationship with
polyamine metabolism Authors: Lescoat, G.1;
Chantrel-Groussard, K.1; Pasdeloup, N.1; Nick, H=2E2; Brissot,
P.1; Gaboriau, F.1
Source: Cell Proliferation, Volume 40, Number 5, October 2007
, pp. 755-767(13)
Publisher: Blackwell Publishing
Abstract:
Objective:=E2=80=82Iron loading has been observed to have a
hyperproliferat= ive effect on hepatocytes in vitro and on
tumour cells in vivo; removal of this iron being required to
induce antitumour activity. Material and
Methods:=E2=80=82Antiproliferative effects of orally active
tridentate iron chelator ICL670 (deferasirox) and bidentate
iron chelator CP20 (deferiprone), mediated through the
chelation of intracellular iron, were compared in rat hepatoma
cell line FAO and human hepatoma cell line HUH7.
Results:=E2=80=82In FAO cell cultures, we have shown that
ICL670 decreased cell viability and DNA replication and
induced apoptosis more efficiently than an iron-binding
equivalent concentration of
CP20. Moreover, ICL670 decreased significantly the number of
the cells in G2-M phase. In the HUH7 cell cultures,
ICL670 and a four-time higher iron-binding equivalent
concentration of CP20, decreased cell viability and DNA
replication in the same range. CP20 increased the number
of the cells in G2-M phase. However, ICL670 inhibited
polyamine biosynthesis by decreasing ornithine
decarboxylase mRNA level; in contrast, CP20 increased
polyamine biosynthesis, particularly putrescine level,
by stimulating spermidine-spermine N1-acetyl transferase
activity that could activate the polyamine retro-
conversion pathway. By mass spectrometry, we observed
that ICL670 cellular uptake was six times higher than
CP20. Conclusions:=E2=80=82These results suggest that
ICL670 has a powerful antitumoural effect and blocks
cell proliferation in neoplastic cells by a pathway
different from that of CP20 and may constitute a
potential adjuvant drug for anticancer therapy. Document
Type: Research article
DOI: 10.1111/j.1365-2184.2007.00468.x
Affiliations: 1: Inserm, U522, Rennes, F-35000 France; Univ
Rennes 1, Rennes, F-35000 France; IFR 140, Rennes, F-35000
France, 2: Novartis Institutes for BioMedical Research, Basel
4002, Switzerland
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk