Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model by Eline Menu, Helena Jernberg-Wiklund,

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Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model by Eline Menu, Helena Jernberg-Wiklund, Thomas Stromberg, Hendrik De Raeve, Leonard Girnita, Olle Larsson, Magnus Axelson, Kewal Asosingh, Kenneth Nilsson, Ben Van Camp, and Karin Vanderkerken Blood Volume 107(2):655-660 January 15, 2006 ©2006 by American Society of Hematology

Inhibition of the downstream pathways of the IGF-1R by PPP Inhibition of the downstream pathways of the IGF-1R by PPP. (A) IGF-1R isolated from 5T33MM cell lysates was incubated with different concentrations of PPP for 30 minutes, before kinase activation. Inhibition of the downstream pathways of the IGF-1R by PPP. (A) IGF-1R isolated from 5T33MM cell lysates was incubated with different concentrations of PPP for 30 minutes, before kinase activation. IGF-1R autophosphorylation was detected by a sandwich ELISA. (B) 5T33MM cells were preincubated with 1 μM PPP for 4 hours before stimulation with IGF-1 (100 ng/mL for 10 minutes). Equivalent amounts of lysates were immunoblotted with anti–P-ERK1/2 and reblotted with anti-ERK1/2 to confirm equal loading. One experiment representative of 3 is shown. Eline Menu et al. Blood 2006;107:655-660 ©2006 by American Society of Hematology

Effects of PPP on IGF-1–induced DNA synthesis and VEGF secretion. Effects of PPP on IGF-1–induced DNA synthesis and VEGF secretion. The 5T33MM cells were stimulated with or without 10 ng/mL IGF-1 (DNA synthesis) and 100 ng/mL (ELISA) after a 30-minute incubation with 1 μM PPP (▪) or not (□). DNA synthesis (A) was measured by a thymidine incorporation assay and VEGF secretion (B) by ELISA. Results are shown relative to unstimulated cells. The maximum IGF-1–stimulated VEGF secretion reaches 250 pg/mL. Mean values ± SD for 3 independent experiments are shown.*P < .02; **P < .05. Eline Menu et al. Blood 2006;107:655-660 ©2006 by American Society of Hematology

Effect of PPP in vivo. Effect of PPP in vivo. (A) Serum paraprotein concentrations as determined by serum electrophoresis. (B) Tumor load as determined by flow cytometric analysis. Data are expressed as percentage 5T33MM cells of total cell number. (C-D) Weight of spleen and liver in grams of naive and treated or untreated 5T33MM-bearing mice. (E) Microvessel density. The number of microvessels in the tibiae and femora of the mice, counted by CD31 staining. Mean values ± SD for groups of 10 mice are shown.*P > .05; **P < .001; ***P < .05; ****P < .02. Eline Menu et al. Blood 2006;107:655-660 ©2006 by American Society of Hematology

Effect of PPP on disease-free survival. Effect of PPP on disease-free survival. Mice were either untreated or treated with 50 mM PPP or the vehicle (DMSO/oil, 9:1) from the day of injection with 5T33MM onward. The first day of onset of morbidity was in the vehicle group on the 17th day. All naive mice were killed on the last day. The PPP group lived 10 days longer (P < .001 between vehicle group and PPP group). Eline Menu et al. Blood 2006;107:655-660 ©2006 by American Society of Hematology