Second-generation TKI dasatinib inhibits proliferation of mesenchymal stem cells and osteoblast differentiation in vitro

Jönsson, Sofia; Hjorth‐Hansen, Henrik; Olsson, Bob; Wadenvik, Hans; Sundan, Anders; Standal, Therese

doi:10.1038/leu.2010.84

Cited by 13 publications

(17 citation statements)

References 18 publications

(45 reference statements)

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“…However, the reported findings significantly disagreed [56]–[58]. Jonsson and colleagues showed that dasatinib inhibits the proliferation of MSC and their bone morphogenetic protein-dependent osteoblastic differentiation [56].…”

Section: Discussionmentioning

confidence: 99%

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The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

et al. 2011

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BackgroundThe introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance.Design and MethodsWe investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs).ResultsOur findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase.ConclusionsOur data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences.

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Section: Discussionmentioning

confidence: 99%

“…During the development of this project, studies describing the effect of dasatinib on human MSCs osteogenesis (but not its adipogenic activity) have been published [56]–[58]. However, the reported findings significantly disagreed [56]–[58].…”

Section: Discussionmentioning

confidence: 99%

The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

et al. 2011

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“…The first studies on the effect of dasatinib on MSCs were published in 2010 [184, 185]. Jonsson and coll., in an investigation published on Leukemia, stated that the molecule inhibits the growth of MSCs and their osteoblastic differentiation [184].…”

Section: Msc and Tk Inhibitorsmentioning

confidence: 99%

Section: Msc and Tk Inhibitorsmentioning

confidence: 99%

“…Jonsson and coll., in an investigation published on Leukemia, stated that the molecule inhibits the growth of MSCs and their osteoblastic differentiation [184]. The antiproliferative activity was correlated to the inhibition of c-Abl, PDGFR, c-src and other kinases [184]. On the other hand, a different group reported that dasatinib stimulated osteogenesis increasing alkaline phosphatase activity and upregulating the expression of bone sialoprotein and Opn [185].…”

Section: Msc and Tk Inhibitorsmentioning

confidence: 99%

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Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

et al. 2016

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The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish “normal” from “transformed” phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the “vanguard” of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment. Other tyrosine kinases have been selected as targets of therapy, but the efficacy of their inhibition, although evident, is less definite. Two major negative effects exist in this therapeutic strategy and are linked to the specificity of the drugs and to the role of the targeted kinase in non-malignant cells. In this review, we will discuss the data available on the TKIs effects on the metabolism and functions of mesenchymal stromal cells (MSCs). MSCs are widely distributed in human tissues and play key physiological roles; nevertheless, they might be responsible for important pathologies. At present, bone marrow (BM) MSCs have been studied in greater detail, for both embryological origins and functions. The available data are evocative of an unexpected degree of complexity and heterogeneity of BM-MSCs. It is conceivable that this grade of intricacy occurs also in MSCs of other organs. Therefore, in perspective, the negative effects of TKIs on MSCs might represent a critical problem in long-term cancer therapies based on such inhibitors.

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Effects of second‐generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors

Tibullo

Barbagallo

Giallongo

et al. 2011

Hematological Oncology

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The BCR-ABL inhibitor imatinib is a standard first-line therapy for patients with chronic myeloid leukemia. However, it has been demonstrated that this long-term treatment is associated with altered bone metabolism. The mechanisms of this effect are not fully understood, but an inhibition of the platelet-derived growth factor receptor (PDGF-R) β axis has been suspected on the basis of some in vitro findings. We evaluated the osteoblastic differentiation of mesenchymal stem cells derived from bone marrow (hBM-MSCs) after in vitro treatment with dasatinib, nilotinib or bosutinib. Human bone marrow mesenchymal stem cells were induced to differentiate in osteoblastic cells by treatment with osteogenic medium with or without dasatinib, nilotinib or bosutinib. We found that the addition of dasatinib, and to a greater extend nilotinib, induced expression of osteogenic mRNA markers as compared with cultures with standard medium or osteogenic medium only. However, treatment with bosutinib did not induce an increase of osteogenic markers. In conclusion, we show that besides imatinib, other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib, but not bosutinib, increase osteogenic markers in hBM-MSCs. Because bosutinib differs from the other TKIs because of its low affinity to other kinases such as PDGF-R, these experiments suggest that inhibition of PDGF-R may be involved in the induction of osteoblastogenesis by TKIs.

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Second-generation TKI dasatinib inhibits proliferation of mesenchymal stem cells and osteoblast differentiation in vitro

Cited by 13 publications

References 18 publications

The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

Effects of second‐generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors

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