Specific roles for the PI3K and the MEK–ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model

Menu, Eline; Kooijman, Ron; Valckenborgh, Els Van; Asosingh, Kewal; Bâkkus, Marleen; Camp, Ben Van; Vanderkerken, Karin

doi:10.1038/sj.bjc.6601613

Cited by 96 publications

(94 citation statements)

References 47 publications

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“…We next asked whether IL-6, VEGF, or BM stroma, previously shown to promote growth and survival of MM cells (Chauhan et al, 1996;Podar et al, 2001;Iwasaki et al, 2002;Menu et al, 2004), would reverse the inhibitory effect of Atiprimod. To investigate this, we plated the BM stroma cell line KM102 in 96-well flatbottomed plates.…”

Section: Atiprimod Inhibits Myeloma Cell Proliferationmentioning

confidence: 99%

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod 5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a timeand dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G 0 /G 1 phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X L , and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

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Section: Atiprimod Inhibits Myeloma Cell Proliferationmentioning

confidence: 99%

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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“…EGF and IGF-1 have been shown to stimulate VEGF-A mRNA expression in various cell lines. [24][25][26][27] We hypothesized that, also in human proximal tubule cells, EGF and IGF-1 might play a crucial role inducing VEGF-A expression. Thus, we investigated the transcription of VEGF-A mRNA in HK-2 cells in the presence of EGF and IGF-1, respectively.…”

Section: Egf and Igf-1 Stimulate Vegf-a Mrna Expression In Renal Proxmentioning

confidence: 99%

Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

Rudnicki

Perco

Enrich

et al. 2009

Laboratory Investigation

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“…Samples were prepared from whole-cell pellets as described earlier. 2 The amount of total protein was quantified using the Bicinchoninic acid protein assay kit (Perbio Science, Bonn, Germany). In all, 40 mg of protein lysates were separated on a 15% SDS-polyacrylamide gel electrophoresis and transferred to PVDF membranes (Bio-Rad, Hercules, CA, USA).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…The MM cells closely interact with the BM microenvironment, which supports their growth, survival and drug resistance through cell-cell adhesion and release of growth factors such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1). 1,2 Neovascularization and osteolysis are processes in the BM microenvironment that are induced by the MM cells, as well as through mutual interactions with the microenvironment and that contribute to the pathogenesis of MM. Neovascularization is induced by an alteration in the balance of pro-and anti-angiogenic factors secreted by both the MM cells and the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

et al. 2009

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Multiple myeloma (MM) is a B-cell malignancy, which often remains incurable because of the development of drug resistance governed by the bone marrow (BM) microenvironment. Novel treatment strategies are therefore urgently needed. In this study, we evaluated the anti-MM activity of JNJ-26481585, a novel 'second-generation' pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor, using the syngeneic murine 5TMM model of MM. In vitro, JNJ-26481585 induced caspase cascade activation and upregulation of p21, resulting in apoptosis and cell cycle arrest in the myeloma cells at low nanomolar concentrations. Similar results could be observed in BM endothelial cells using higher concentrations, indicating the selectivity of JNJ-26481585 toward cancer cells. In a prophylactic and therapeutic setting, treatment with JNJ-26481585 resulted in an almost complete reduction of the tumor load and a significant decrease in angiogenesis. 5T2MM-bearing mice also developed a MM-related bone disease, characterized by increased osteoclast number, development of osteolytic lesions and a reduction in cancellous bone. Treatment of these mice with JNJ-264815 significantly reduced the development of bone disease. These data suggest that JNJ-26481585 has a potent anti-MM activity that can overcome the stimulatory effect of the BM microenvironment in vivo making this drug a promising new anti-MM agent.

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Specific roles for the PI3K and the MEK–ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model

Cited by 96 publications

References 47 publications

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

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