Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model
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Thorsten Heilmann1,2, Anna-Lena Rumpf3, Marijke Roscher3
1Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24105, Kiel, Germany. thorsten.heilmann@uksh.de.
Purpose:
Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception.
Methods:
An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity.
Results:
Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts.
Conclusion:
Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.
Insights
Dasatinib effectively reduced bone metastases in triple-negative breast cancer (TNBC) models by inhibiting c-Src kinase activity. The drug also improved bone density and reduced osteoclast activity, suggesting its potential for treating bone metastasis and preserving bone health.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bone metastasis is a significant complication of breast cancer, particularly triple-negative breast cancer (TNBC).
- The c-Src kinase pathway plays a crucial role in the development of bone metastasis.
- The interplay between TNF-related apoptosis inducing ligand (TRAIL) and its receptors is emerging in the context of bone metastasis.
Purpose of the Study:
- To investigate the efficacy of Dasatinib, a Src kinase inhibitor, in an in vitro and in vivo model of TNBC bone metastasis.
- To evaluate the impact of Dasatinib on skeletal metastasis, bone volume, bone density, and osteoclast activity.
- To explore the effects of Dasatinib on TRAIL receptor expression.
Main Methods:
- Utilized an osteotropic MDA-MB-231 cell line to establish a TNBC bone metastasis model.
- Administered Dasatinib in vitro and in vivo (xenograft mouse model) to assess its therapeutic effects.
- Analyzed skeletal metastases using bioluminescence imaging and bone changes via micro-computed tomography (µ-CT) and ex vivo bone section analysis.
Main Results:
- Dasatinib inhibited MDA-MB-231 cell proliferation in vitro and induced a shift towards oncogenic TRAIL-R2 expression.
- In vivo, Dasatinib treatment significantly reduced the incidence of skeletal metastases in mice.
- Dasatinib administration led to increased bone volume and density, coupled with decreased osteoclast activity.
Conclusions:
- Dasatinib demonstrates therapeutic potential for targeting early-stage bone metastatic TNBC.
- Dasatinib treatment may help sustain bone health in patients with TNBC bone metastasis.
