Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis

Vandyke, Kate; Dewar, Andrea L.; Farrugia, Amanda N.; Fitter, Stephen; To, Luen Bik; Hughes, Timothy P.; Zannettino, Andrew C.W.

doi:10.1038/leu.2008.356

Cited by 51 publications

(38 citation statements)

References 13 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: 52%

“…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: 52%

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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“…A non-receptor tyrosine kinase Src plays an important role in breast cancer bone metastasis and osteoclastogenesis (Hiscox et al, 2010). Src inhibitor dasatinib that used in chronic myelogenous leukemia also inhibits osteoclastogenesis in vitro (Vandyke et al, 2009). Other src inhibitor saracatinib decreased bone resorption markers in a phase I study (Hannon et al, 2012).…”

Section: Advances In Treatment Of Bone Metastasimentioning

confidence: 99%

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

Erdoğan

Çiçin²

2014

Asian Pacific Journal of Cancer Prevention

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Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice. It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threatening hypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules play roles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts should be directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to first skeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with no bone metastasis, and also do not prolong survival. The receptor activator for nuclear factor kB ligand inhibitor denosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides are another treatment option for bone pain. New targeted therapies and radionuclides are still under investigation. In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients.

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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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Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis

Cited by 51 publications

References 13 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

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

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

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