Targeting the GH/IGF-1 axis with novel, small molecule inhibitors
Author: Rosengren, Linda
Date: 2007-10-26
Location: Lars Leksells auditorium, Medicinhistoriska Museet/Eugeniahemmet, Karolinska Universitetssjukhuset, Solna ,Stockholm
Time: 09.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
View/ Open:
thesis.pdf (1.067Mb)
Abstract
The growth hormone (GH) / insulin-like growth factor (IGF) family of
ligands, binding proteins and receptors play multiple roles in cell
growth, metabolism and development. In addition, numerous studies have
demonstrated the pathophysiological importance of the GH/IGF-1 axis. In
particular, the impact of IGF-1 receptor (IGF-1R) in cancer has attracted
increasing attention during the last decade. Several classes of
pharmacological agents that inhibit GH/IGF-1 signaling at different
levels have shown anticancer activity both in vitro and in vivo. GH
receptor (GHR) antagonists have proven the most effective and safe way to
pharmacologically treat overproduction of GH (acromegaly) and antibodies
against the IGF-1R cause massive apoptosis in vitro and tumor regression
in animal models. However, there is a need to develop low molecular
weight compounds targeting the GH/IGF-1 axis which can be administered
perorally and have increased bioavailability compared to protein drugs.
In paper I, we present a new mRNA quantification method which was used to
test a number of low molecular weight compounds for their ability to
reduce GH-induced IGF-1 mRNA in primary hepatocytes. One such potential
GHR antagonist, BVT-A, was selected, and in paper II its attenuating
effect on several markers for GH/IGF-1 overactivity was verified in an
animal model of acromegaly. Picropodophyllin (PPP) was discovered some
years ago as an effective inhibitor of IGF-1R signaling in cell lines and
tumor repressor in vivo. The mechanism by which PPP caused this effect
has not been fully delineated. In paper III, we show that IGF-1R knockout
cells at late passages can acquire IGF-1R expression and dependency and
therefore become sensitive to PPP treatment. Paper IV describes the
inhibitory effect of PPP on IGF-1 induced vascular endothelial growth
factor (VEGF) production as well as on neovascularization of the choroid
in a model of macular degeneration, the most common cause of blindness.
In paper V we show that PPP induces downregulation of the IGF-1R. This
effect is important since it is known that downregulation, not only
deactivation of the receptor is necessary for induction of massive
apoptosis. Finally, in paper VI we show that PPP recruits the E3 ligase
Mdm2 and â-Arrestin1 to the IGF-1R. This action was found to be involved
in receptor downregulation and inhibition of AKT signaling and suggests
that PPP acts as a â-Arrestin1-biased IGF-1R agonist. Hopefully, the
substances identified and evaluated in this thesis will function as lead
compounds in the development of improved pharmaceutical agents against
GH/IGF-1 dependent diseases.
List of papers:
I. Rosengren L, Simko H, Aryan L, Axelsson-Lendin P, Chmielewska J, Mode A, Parrow V (2005). "Antisense and sense RNA probe hybridization to immobilized crude cellular lysates: a tool to screen growth hormone antagonists." J Biomol Screen 10(3): 260-9.
Pubmed
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II. Rosengren L, Parrow V, Chmielewska J, Mode A, Fhölenhag K (2007). "In vivo evaluation of a novel, orally bioavailable, small molecule growth hormone receptor antagonist." Growth Horm IGF Res 17(1): 47-53.
Pubmed
View record in Web of Science®
III. Rosengren L, Vasilcanu D, Vasilcanu R, Fickenscher S, Sehat B, Natalishvili N, Naughton S, Yin S, Girnita A, Girnita L, Axelson M, Larsson O (2006). "IGF-1R tyrosine kinase expression and dependency in clones of IGF-1R knockout cells (R-)." Biochem Biophys Res Commun 347(4): 1059-66.
Pubmed
View record in Web of Science®
IV. Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, Van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A (2007). "Inhibition of VEGF secretion and choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor." Invest Ophtamol Vis Sci. [Accepted]
Pubmed
View record in Web of Science®
V. Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O (2007). "Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and beta-arrestin1." Oncogene Sep 10: Epub ahead of print
Pubmed
View record in Web of Science®
VI. Rosengren L, Girnita L, Axelson M, Larsson O (2007). "Picropodophyllin (PPP) acts as a beta-Arrestin1-biased IGF-1R agonist." [Submitted]
I. Rosengren L, Simko H, Aryan L, Axelsson-Lendin P, Chmielewska J, Mode A, Parrow V (2005). "Antisense and sense RNA probe hybridization to immobilized crude cellular lysates: a tool to screen growth hormone antagonists." J Biomol Screen 10(3): 260-9.
Pubmed
View record in Web of Science®
II. Rosengren L, Parrow V, Chmielewska J, Mode A, Fhölenhag K (2007). "In vivo evaluation of a novel, orally bioavailable, small molecule growth hormone receptor antagonist." Growth Horm IGF Res 17(1): 47-53.
Pubmed
View record in Web of Science®
III. Rosengren L, Vasilcanu D, Vasilcanu R, Fickenscher S, Sehat B, Natalishvili N, Naughton S, Yin S, Girnita A, Girnita L, Axelson M, Larsson O (2006). "IGF-1R tyrosine kinase expression and dependency in clones of IGF-1R knockout cells (R-)." Biochem Biophys Res Commun 347(4): 1059-66.
Pubmed
View record in Web of Science®
IV. Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, Van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A (2007). "Inhibition of VEGF secretion and choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor." Invest Ophtamol Vis Sci. [Accepted]
Pubmed
View record in Web of Science®
V. Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O (2007). "Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and beta-arrestin1." Oncogene Sep 10: Epub ahead of print
Pubmed
View record in Web of Science®
VI. Rosengren L, Girnita L, Axelson M, Larsson O (2007). "Picropodophyllin (PPP) acts as a beta-Arrestin1-biased IGF-1R agonist." [Submitted]
Issue date: 2007-10-05
Rights:
Publication year: 2007
ISBN: 978-91-7357-346-7
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