Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor

Brownlow, Nicola; Mol, Clifford D.; Hayford, Claudia; Ghaem‐Maghami, Sadaf; Dibb, Nick J.

doi:10.1038/leu.2008.237

Cited by 58 publications

(57 citation statements)

References 24 publications

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“…(35)(36)(37)(38) While the precise mechanism(s) remain(s) to be elucidated, data shown here (Fig. 1) and previously (7,8) suggest that dasatinib inhibits in vitro osteoclastogenesis at concentrations at which cfms but not c-Src is affected. This suggests that inhibition of cfms, but not c-Src, contributes to the antiosteoclastic effects of dasatinib treatment in vitro.…”

Section: Discussionsupporting

confidence: 54%

“…1). (7,8) c-fms and c-Src are two known dasatinib targets that play a crucial role in bone remodeling by OCs. Binding of M-CSF to its receptor, c-fms, regulates the proliferation and survival of OC precursors and mature OCs (30) and induces cell migration and cytoplasmic spreading.…”

Section: Discussionmentioning

confidence: 99%

“…(7,8) To confirm that rat OCs were sensitive to dasatinib, we examined the effect of dasatinib on OC formation and activity in rat bone marrow cultures in vitro. A significant decrease in the number of TRACP þ multinucleated cells was observed at 1.25 nM dasatinib ( p < .05; Fig.…”

Section: In Vitro Oc Formation and Activitymentioning

confidence: 99%

“…Treatment with dasatinib at clinically relevant concentrations inhibits the formation and activity of tartrate-resistant acid phosphatase (TRACP)-positive OCs from human peripheral blood mononuclear cells and primary mouse bone marrow cells in vitro. (7,8) It remains to be determined what effect this may have on bone remodeling in patients undergoing dasatinib treatment.…”

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confidence: 99%

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The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 mg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib-or ZOL-treated animals relative to controls. However, micro-computed tomographic (mCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. ß

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: In Vitro Oc Formation and Activitymentioning

confidence: 99%

mentioning

confidence: 99%

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The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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“…Dasatinib inhibits the production of osteoclasts and tumor-associated macrophages, as well as the functional activities of osteoclasts, platelets, T cells and natural killer cells. [3][4][5][6][7] As these cell types do not express BCR-ABL, inhibition of SFK members such as LYN, or other kinase targets, is likely responsible for the effects of dasatinib on these cells.…”

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confidence: 99%

Dasatinib promotes ATRA-induced differentiation of AML cells

et al. 2009

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are sensitive to NMD in primary AML. Consequently, these AML cases do not express the predicted truncated WT1 proteins. In these AML cases, mutations in WT1 may result in haploinsufficiency rather than expression of truncated WT1 proteins with impaired function. Haploinsufficiency and impaired function have been proposed as two possible mechanisms by which mutant WT1 may affect normal hematopoietic development. Surprisingly, in the WT1 mutant AML cases the wild-type WT1 protein is expressed at relatively high levels. Although, this phenomena has been shown in sporadic Wilms' tumors and some related syndromes, it is currently unclear whether the WT1 protein is pathogenic in these cases or whether it is related to the etiology of the cell of origin. 1

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The multi‐kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis

Yoshikawa

Abe

2021

Cell Biochemistry & Function

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Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that presents with bone destruction and pain. Although genetic studies have identified signalling pathways involving CRMO, molecularly targeted drugs remain unavailable. We used an animal model of CRMO as an in vivo screening system for candidate therapeutic agents. A gain‐of‐function mutation in Fgr, a member of Src family kinases (SFKs), causes peripheral paw inflammation and reduced bone mineral density (BMD) in Ali18 mice. The SFK inhibitor dasatinib was selected for administration to Ali18 mice daily for 2 weeks. Local inflammation and BMD were assessed by clinical scoring and computed tomography, respectively. Pilot studies in a small number of animals showed that dasatinib administration effectively suppressed the early phase of autoinflammation in Ali18 mice. Serial oral gavage of dasatinib to a group of Ali18 mice confirmed significant suppression of paw swelling with no side effects. Histological analysis revealed that abnormal proliferative bone marrow cells and inflammatory infiltration into the skin in the affected area were clearly reduced in the animals with dasatinib administration. Further, trabecular BMD in Ali18 long bones was restored to levels similar to that found in wild type mice. Our results indicate that autoinflammation and related‐bone phenotypes were completely suppressed by the dasatinib kinase inhibitor in CRMO model animals. Thus, it is strongly suggested that dasatinib can be used for clinical treatments of CRMO with the combination of molecular diagnosis of the FGR locus. Significance of the study Autoinflammation and related‐bone phenotypes were effectively suppressed by the kinase inhibitor dasatinib in CRMO model animals. In combination with molecular analysis of the FGR locus, dasatinib is a strong candidate for the clinical treatments of CRMO. We propose that the animal model employed in this study can be used to screen this and other potential drugs for CRMO.

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Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor

Cited by 58 publications

References 24 publications

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Dasatinib promotes ATRA-induced differentiation of AML cells

The multi‐kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis

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