Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway

Recchia, Irene; Rucci, Nadia; Funari, Alessia; Migliaccio, Silvia; Taranta, Anna; Longo, Maurizio; Kneissel, Michaela; Šuša, Mira; Fabbro, Doriano; Teti, Anna

doi:10.1016/j.bone.2003.06.004

Cited by 65 publications

(40 citation statements)

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“…A potential therapeutic impact could be predicted from these results, hypothesizing that a c-Src inhibitor could be used in cancer-induced bone diseases not only to impair osteoclast bone resorption and tumour cell proliferation 17,26,27 , but also to reduce IL-6 production and, therefore, its deleterious systemic effects on the body. Indeed, clinical trials are in progress for cancer using the c-Src inhibitor Saracatinib, which, in our opinion, associated with the IL-6 receptor-neutralizing antibody Tucilizumab, may open new avenues for combination treatment of patients.…”

Section: Discussionmentioning

confidence: 99%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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Interleukin-6 (IL-6) and c-src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-src stimulates IL-6 expression through the sTAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.

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Section: Discussionmentioning

confidence: 99%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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“…Further support of src involvement in the regulation of osteoclast activity is demonstrated by the osteopetrotic phenotype observed in src knockout mice despite morphologically normal appearing osteoclasts (Soriano et al, 1991). Additionally, src inhibition was also reported to increase apoptosis of mature osteoclasts both in vitro and in vivo (Recchia et al, 2004).…”

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confidence: 87%

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

et al. 2009

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BACKGROUND: Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone. METHODS: C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed. RESULTS: Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3 ± 0.4 vs 9.2 ± 2.1 (P ¼ 0.004). Combination therapy improved efficacy over dasatinib alone (P ¼ 0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (Po0.001). CONCLUSION: Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.

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“…[20][21][22] Disruption of Src signaling reduces the number of osteoclasts both in vitro and in vivo. 23 A further role for Src in osteoclast biology is in maintenance of osteoclast energy stores by phosphorylating mitochondrial cytochrome c oxidase. 8 Although Src has positive effects on osteoclasts, its effects on osteoblasts are generally negative.…”

Section: Src Family Kinases and Normal Bone Functionmentioning

confidence: 99%

Targeting Src signaling in metastatic bone disease

Araujo¹,

Logothetis²

2008

Intl Journal of Cancer

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Src is a tyrosine kinase involved in the regulation of a range of cellular processes including proliferation, adhesion, motility and survival. In addition, it is a key regulator of bone metabolism. Src has been implicated in the pathogenesis of a number of cancers, and has been found to be overexpressed in breast, prostate, colorectal, pancreatic and nonsmall-cell lung tumors. There is also evidence that aberrant Src signaling may contribute to the increased osteoclastic activity associated with bone metastases. Bone metastases frequently occur in cancer patients with advanced disease. The metastasized cells disrupt normal bone remodeling pathways resulting in the release of growth factors that further promote tumor growth. Thus, a cycle of metastatic bone destruction is initiated, leading to compromised skeletal integrity and substantially reduced quality of life. Because of the role of Src in both cancer development and in bone metabolism, it may provide a therapeutic target for patients with bone metastases. ' 2008 Wiley-Liss, Inc.Key words: Src signaling; tyrosine kinase; bone metastases; osteoclasts Bone involvement in advanced cancerBone metastases are common in several cancers, including breast, prostate, colorectal and lung cancer. In addition, nearly all patients with multiple myeloma experience bone lesions. 1 Although bone resorption by osteoclasts and synthesis of new bone by osteoblasts is tightly regulated in normal bone metabolism, malignant cells dysregulate the bone remodeling process. The chronic presence of bone metastases often results in complete pathologic remodeling of the affected bone compartment.If untreated, bone metastases lead to skeletal complications such as fractures, spinal cord compression and bone pain, all of which may profoundly reduce patients' quality of life. Therefore, early diagnosis and adequate treatment of bone metastases is critically important.Cancer patients are also at risk of bone loss as a result of certain cancer therapies. In premenopausal women, chemotherapy can cause ovarian failure, leading to early menopause and rapid bone loss. 2 Adjuvant endocrine therapies that deplete peripheral sex hormone production can also reduce bone mass. Bone loss is also frequently seen in men receiving androgen-deprivation therapy for prostate cancer, leading to an increased risk of osteoporotic fracture. 3 Molecular biology of Src family kinasesSrc (encoded by the c-src gene) is a nonreceptor tyrosine kinase localized to the cellular membrane, involved in the regulation of a range of cellular processes, including proliferation, adhesion, motility and survival (for a review see Yeatman or Rucci et al. 4,5 ). It is the best-characterized member of the Src family kinases (SFKs), a family of 9 similar proteins that also includes Blk, Fgr, Fyn, Hck, Lck, Lyn, Yes and Yrk. 4,5 SFK members share a unique domain and 3 other domains termed the kinase domain and Src homology (SH) domains SH2 and SH3. The kinase domain phosphorylates tyrosine residues in substrates that bind to the SH...

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Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway

Cited by 65 publications

References 69 publications

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

Targeting Src signaling in metastatic bone disease

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