Cancer Research 09 AM Call for Abstracts SU2C
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Girnita, A.
Right arrow Articles by Axelson, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Girnita, A.
Right arrow Articles by Axelson, M.
[Cancer Research 64, 236-242, January 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Cyclolignans as Inhibitors of the Insulin-Like Growth Factor-1 Receptor and Malignant Cell Growth

Ada Girnita1, Leonard Girnita1, Fabrizio del Prete3, Armando Bartolazzi3, Olle Larsson1 and Magnus Axelson2

1Department of Oncology and Pathology, Cancer Center Karolinska and 2Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden, and 3Laboratory of Immunology Regina Elena Cancer Institute and Department of Pathology, Sant Andrea University Hospital, Rome, Italy

The insulin-like growth factor-1 receptor (IGF-1R) plays a pivotal role in transformation, growth, and survival of malignant cells, and has emerged as a general and promising target for cancer treatment. However, no fully selective IGF-1R inhibitors have thus far been found. This is explained by the fact that IGF-1R is highly homologous to the insulin receptor, coinhibition of which may cause diabetic response. The receptors are both tyrosine kinases, and their ATP binding sites are identical, implying that ATP inhibitors cannot discriminate between them. Therefore, the current strategy has been to identify compounds interfering with receptor autophosphorylation at the substrate level. In this study we investigated the effects of cyclolignans and related molecules on IGF-1R activity. We report that certain cyclolignans are potent and selective inhibitors of tyrosine phosphorylation of the IGF-1R. Of particular interest was picropodophyllin (PPP), which is almost nontoxic (LD50 >500 mg/kg in rodents). PPP efficiently blocked IGF-1R activity, reduced pAkt and phosphorylated extracellular signal regulated kinase 1 and 2 (pErk1/2), induced apoptosis in cultured IGF-1R-positive tumor cells, and caused complete tumor regression in xenografted and allografted mice. PPP did not affect the insulin receptor or compete with ATP in an in vitro kinase assay, suggesting that it may inhibit IGF-1R autophosphorylation at the substrate level. This is also in agreement with our molecular model of how the cyclolignans may act on the IGF-1R kinase. Our results open the possibility to use PPP or related compounds with inhibitory effects on IGF-1R as lead compounds in development of anticancer agents.




This article has been cited by other articles:


Home page
 IOVSHome page
M. A. Economou, S. Andersson, D. Vasilcanu, C. All-Ericsson, E. Menu, A. Girnita, L. Girnita, M. Axelson, S. Seregard, and O. Larsson
Oral Picropodophyllin (PPP) Is Well Tolerated In Vivo and Inhibits IGF-1R Expression and Growth of Uveal Melanoma
Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2337 - 2342.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. A. Economou, J. Wu, D. Vasilcanu, L. Rosengren, C. All-Ericsson, I. van der Ploeg, E. Menu, L. Girnita, M. Axelson, O. Larsson, et al.
Inhibition of VEGF Secretion and Experimental Choroidal Neovascularization by Picropodophyllin (PPP), an Inhibitor of the Insulin-like Growth Factor-1 Receptor
Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2620 - 2626.
[Abstract] [Full Text] [PDF]

Home page
 aacredbookHome page
D. Sachdev and D. Yee
Disrupting Insulin-Like Growth Factor Signaling as a Potential Cancer Therapy
Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 39 - 58.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. Vasilcanu, D. Vasilcanu, B. Sehat, S. Yin, A. Girnita, M. Axelson, and L. Girnita
Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin
Mol. Pharmacol., March 1, 2008; 73(3): 930 - 939.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Zhu and J. W. Pollard
Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling
PNAS, October 2, 2007; 104(40): 15847 - 15851.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Fulzele, D. J. DiGirolamo, Z. Liu, J. Xu, J. L. Messina, and T. L. Clemens
Disruption of the Insulin-like Growth Factor Type 1 Receptor in Osteoblasts Enhances Insulin Signaling and Action
J. Biol. Chem., August 31, 2007; 282(35): 25649 - 25658.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Girnita, S. K. Shenoy, B. Sehat, R. Vasilcanu, D. Vasilcanu, A. Girnita, R. J. Lefkowitz, and O. Larsson
beta-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression
J. Biol. Chem., April 13, 2007; 282(15): 11329 - 11338.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Linder, M. C. Shoshan, and R. S. Gupta
Picropodophyllotoxin or Podophyllotoxin Does Not Induce Cell Death via Insulin-like Growth Factor-I Receptor
Cancer Res., March 15, 2007; 67(6): 2899 - 2899.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
O. Larsson and M. Axelson
Cyclolignans as Inhibitors of the Insulin-like Growth Factor-I Receptor
Cancer Res., March 15, 2007; 67(6): 2899 - 2899.
[Full Text] [PDF]

Home page
 BloodHome page
L. Conti, G. Regis, A. Longo, P. Bernabei, R. Chiarle, M. Giovarelli, and F. Novelli
In the absence of IGF-1 signaling, IFN-{gamma} suppresses human malignant T-cell growth
Blood, March 15, 2007; 109(6): 2496 - 2504.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. C. Manara, L. Landuzzi, P. Nanni, G. Nicoletti, D. Zambelli, P. L. Lollini, C. Nanni, F. Hofmann, C. Garcia-Echeverria, P. Picci, et al.
Preclinical In vivo Study of New Insulin-Like Growth Factor-I Receptor-Specific Inhibitor in Ewing's Sarcoma
Clin. Cancer Res., February 15, 2007; 13(4): 1322 - 1330.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Zhang, A. M. Pelzer, D. T. Kiang, and D. Yee
Down-regulation of Type I Insulin-like Growth Factor Receptor Increases Sensitivity of Breast Cancer Cells to Insulin
Cancer Res., January 1, 2007; 67(1): 391 - 397.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
D. Sachdev and D. Yee
Disrupting insulin-like growth factor signaling as a potential cancer therapy
Mol. Cancer Ther., January 1, 2007; 6(1): 1 - 12.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
E. Colon, F. Zaman, M. Axelson, O. Larsson, C. Carlsson-Skwirut, K. V. Svechnikov, and O. Soder
Insulin-Like Growth Factor-I Is an Important Antiapoptotic Factor for Rat Leydig Cells during Postnatal Development
Endocrinology, January 1, 2007; 148(1): 128 - 139.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
J Riedemann and V M Macaulay
IGF1R signalling and its inhibition
Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S33 - S43.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S.-B. Catrina, I. R. Botusan, A. Rantanen, A. I. Catrina, P. Pyakurel, O. Savu, M. Axelson, P. Biberfeld, L. Poellinger, and K. Brismar
Hypoxia-Inducible Factor-1{alpha} and Hypoxia-Inducible Factor-2{alpha} Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I
Clin. Cancer Res., August 1, 2006; 12(15): 4506 - 4514.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Z. Wang, G. Chakravarty, S. Kim, Y. D. Yazici, M. N. Younes, S. A. Jasser, A. A. Santillan, C. D. Bucana, A. K. El-Naggar, and J. N. Myers
Growth-Inhibitory Effects of Human Anti-Insulin-Like Growth Factor-I Receptor Antibody (A12) in an Orthotopic Nude Mouse Model of Anaplastic Thyroid Carcinoma
Clin. Cancer Res., August 1, 2006; 12(15): 4755 - 4765.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. Girnita, C. All-Ericsson, M. A. Economou, K. Astrom, M. Axelson, S. Seregard, O. Larsson, and L. Girnita
The Insulin-Like Growth Factor-I Receptor Inhibitor Picropodophyllin Causes Tumor Regression and Attenuates Mechanisms Involved in Invasion of Uveal Melanoma Cells
Clin. Cancer Res., February 15, 2006; 12(4): 1383 - 1391.
[Abstract] [Full Text] [PDF]

Home page
 J Biomol ScreenHome page
K. Y. Horiuchi, Y. Wang, S. L. Diamond, and H. Ma
Microarrays for the Functional Analysis of the Chemical-Kinase Interactome
J Biomol Screen, February 1, 2006; 11(1): 48 - 56.
[Abstract] [PDF]

Home page
 BloodHome page
E. Menu, H. Jernberg-Wiklund, T. Stromberg, H. De Raeve, L. Girnita, O. Larsson, M. Axelson, K. Asosingh, K. Nilsson, B. Van Camp, et al.
Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model
Blood, January 15, 2006; 107(2): 655 - 660.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
T. Stromberg, S. Ekman, L. Girnita, L. Y. Dimberg, O. Larsson, M. Axelson, J. Lennartsson, U. Hellman, K. Carlson, A. Osterborg, et al.
IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells
Blood, January 15, 2006; 107(2): 669 - 678.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Girnita, S. K. Shenoy, B. Sehat, R. Vasilcanu, A. Girnita, R. J. Lefkowitz, and O. Larsson
{beta}-Arrestin Is Crucial for Ubiquitination and Down-regulation of the Insulin-like Growth Factor-1 Receptor by Acting as Adaptor for the MDM2 E3 Ligase
J. Biol. Chem., July 1, 2005; 280(26): 24412 - 24419.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
E. Ulfarsson, A. Karstrom, S. Yin, A. Girnita, D. Vasilcanu, M. Thoren, G. Kratz, J. Hillman, M. Axelson, O. Larsson, et al.
Expression and Growth Dependency of the Insulin-Like Growth Factor I Receptor in Craniopharyngioma Cells: A Novel Therapeutic Approach
Clin. Cancer Res., July 1, 2005; 11(13): 4674 - 4680.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Miyamoto, M. Nakamura, K. Shitara, K. Nakamura, Y. Ohki, G. Ishii, M. Goya, K. Kodama, T. Sangai, H. Maeda, et al.
Blockade of Paracrine Supply of Insulin-Like Growth Factors Using Neutralizing Antibodies Suppresses the Liver Metastasis of Human Colorectal Cancers
Clin. Cancer Res., May 1, 2005; 11(9): 3494 - 3502.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
G. S. Warshamana-Greene, J. Litz, E. Buchdunger, C. Garcia-Echeverria, F. Hofmann, and G. W. Krystal
The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy
Clin. Cancer Res., February 15, 2005; 11(4): 1563 - 1571.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
E. Colon, K. V. Svechnikov, C. Carlsson-Skwirut, P. Bang, and O. Soder
Stimulation of Steroidogenesis in Immature Rat Leydig Cells Evoked by Interleukin-1{alpha} Is Potentiated by Growth Hormone and Insulin-Like Growth Factors
Endocrinology, January 1, 2005; 146(1): 221 - 230.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. Ahlen, J. Wejde, O. Brosjo, A. von Rosen, W.-H. Weng, L. Girnita, O. Larsson, and C. Larsson
Insulin-Like Growth Factor Type 1 Receptor Expression Correlates to Good Prognosis in Highly Malignant Soft Tissue Sarcoma
Clin. Cancer Res., January 1, 2005; 11(1): 206 - 216.
[Abstract] [Full Text] [PDF]

Home page
 ASH ANNUAL MEETING ABSTRACTSHome page
T. Stromberg, S. Ekman, L. Girnita, J. Lennartsson, U. Hellman, K. Carlson, A. Osterborg, K. Vanderkerken, M. Axelson, O. Larsson, et al.
Targeting the Insulin-Like Growth Factor-I Receptor (IGF-IR) in Multiple Myeloma Cells Using Selective IGF-IR Tyrosine Kinase Inhibitors.
Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 639 - 639.
[Abstract]

Home page
 ASH ANNUAL MEETING ABSTRACTSHome page
K. Vanderkerken, E. Menu, T. Stromberg, H. De Raeve, K. Asosingh, B. Van Camp, and H. Jernberg-Wiklund
Inhibiting the IGF-1 Receptor Tyrosine Kinase with Picropodophillin: An In Vitro and In Vivo Study in the 5T33MM Mouse Model.
Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 640 - 640.
[Abstract]

Home page
 Cancer Res.Home page
K. Breuhahn, S. Vreden, R. Haddad, S. Beckebaum, D. Stippel, P. Flemming, T. Nussbaum, W. H. Caselmann, B. B. Haab, and P. Schirmacher
Molecular Profiling of Human Hepatocellular Carcinoma Defines Mutually Exclusive Interferon Regulation and Insulin-Like Growth Factor II Overexpression
Cancer Res., September 1, 2004; 64(17): 6058 - 6064.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
C. All-Ericsson, L. Girnita, A. Muller-Brunotte, B. Brodin, S. Seregard, A. Ostman, and O. Larsson
c-Kit-Dependent Growth of Uveal Melanoma Cells: A Potential Therapeutic Target?
Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2075 - 2082.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2004 by the American Association for Cancer Research.