Targeting the IGF‐1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: Beneficial effects on tumor growth, angiogenesis, bone disease and survival

Menu, Eline; Jernberg-Wiklund, Helena; Raeve, Hendrik De; Leenheer, Evy De; Coulton, Les; Gallagher, Orla; Valckenborgh, Els Van; Larsson, Olle; Axelson, Magnus; Nilsson, Kenneth; Camp, Ben Van; Croucher, Peter I.; Vanderkerken, Karin

doi:10.1002/ijc.22845

Cited by 55 publications

(75 citation statements)

References 22 publications

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“…PPP did, however, not affect growth of established R-vsrc (IGF-1RÀ/À) tumor grafts , suggesting selectivity for IGF-1R regarding tumor growth. Furthermore, perorally administered PPP was recently shown to drastically prolong survival of a multiple myeloma mouse model, which was treated up to 150 days (Menu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Vasilcanu

Rosengren

et al. 2007

Oncogene

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The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth and survival of malignant cells. Experience in targeting IGF-1R in cancer models has shown that strategies promoting downregulation of the receptor are much more efficient in inducing apoptosis than those inhibiting the IGF-1R activity. Recently, we found that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation of downstream signaling without interfering with the highly homologous insulin receptor (IR). Furthermore, PPP treatment caused strong regression of tumor grafts and prolonged survival of animals with systemic tumor disease. Here we demonstrate that PPP also downregulates the IGF-1R, whereas the IR and several other receptors were not affected. PPP-induced IGF-1R downregulation required expression of the MDM2 E3 ligase, which recently was found to ubiquitinate and cause degradation of the IGF-1R. In addition knockdown of barrestin1, the adaptor molecule known to bridges MDM2 and IGF-1R, prevented downregulation of the receptor and significantly decreased PPP-induced cell death. All together these data suggest that PPP downregulates IGF-1R by interfering with the action of b-arrestin1/MDM2 as well as the achieved receptor downregulation contributes to the apoptotic effect of PPP.

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Section: Introductionmentioning

confidence: 99%

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Vasilcanu

Rosengren

et al. 2007

Oncogene

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“…PPP impairs IGF-1-induced IGF-1R phosphorylation in tumor cells in vitro and in vivo, decreases Akt activity, and causes malignant cell death, leading to tumor regression Menu et al, 2006Menu et al, , 2007.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study shows that PPP drastically prolongs the survival in an animal model of multiple myeloma. The animals were treated daily up to 150 days, and survival was prolonged with almost 3 months compared with the control group (Menu et al, 2007). Despite having a high antitumor efficacy, PPP is apparently also well-tolerated in vivo.…”

mentioning

confidence: 99%

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

Vasilcanu

Vasilcanu²,

Sehat³

et al. 2007

Mol Pharmacol

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The initial event upon binding of insulin-like growth factor 1 to the insulin-like growth factor type-I receptor (IGF-1R) is autophosphorylation of tyrosine residues within the activation loop of the kinase domain followed by phosphorylation of other receptor tyrosine residues and the subsequent activation of the intracellular signaling cascades. We found recently that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and phosphatidyl-3 kinase/Akt (protein kinase B) signaling molecules without interfering with the highly homologous insulin receptor. Furthermore, PPP causes regression of tumor grafts and substantially prolongs the survival of animals with systemic tumor disease. It is of interest that we show here that short treatments with PPP activate the intracellular extracellular signal-regulated kinase (ERK) signaling. Our data suggest that PPP induces IGF-1R ubiquitination and in turn activates ERK1/2. The PPP-induced ERK activation requires IGF-1R because PPP is not able to induce ERK phosphorylation in IGF-1R-negative cells or in cells in which the receptor is knocked down by small interfering RNA. Moreover, in the absence of Mdm2, an E3 ligase that has been shown previously to be involved in IGF-1R ubiquitination, the phosphorylation of ERK did not occur. Thus, apart from inhibiting the receptor activity, PPP can induce IGF-1R ubiquitination and stimulate ERK in an Mdm2-dependent manner. This response could contribute to the apoptotic effect of PPP.

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“…This agent has been shown to induce tumor regression and inhibition of metastasis in several models of human cancer. [84][85][86][87] PPP does not affect the tumor growth of established xenografts composed of IGF-IR-negative cells, whereas IGF-IR-positive xenografts are fully responsive. Recent studies showed that oral PPP is well tolerated in vivo and inhibits IGF-IR expression and growth of melanomas.…”

Section: Igf-ir-targeted Therapymentioning

confidence: 95%

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi

Ito

2011

Biological & Pharmaceutical Bulletin

144

113

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The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.

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Targeting the IGF‐1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: Beneficial effects on tumor growth, angiogenesis, bone disease and survival

Cited by 55 publications

References 22 publications

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

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

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

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