Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model

Heilmann, Thorsten; Rumpf, Anna-Lena; Roscher, M.; Tietgen, Maren; Will, Olga; Gerle, Mirko; Damm, Timo; Borzikowsky, Christoph; Maass, Nicolaì; Glüer, Claus-Christian; Tiwari, Sanjay; Trauzold, Anna; Schem, Christian

doi:10.1007/s00404-020-05496-4

Cited by 11 publications

(8 citation statements)

References 48 publications

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“…The most marked effect of dasatinib was observed in its ability to protect from cartilage destruction and bone erosion. These findings are in line with previous reports supporting that dasatinib demonstrates convergent bone anabolic [32] and reduced bone resorption effects [32], osteoclast inhibitory functions [54], enhancement of chondrogenesis [55] as well as enhanced bone preservation in metastatic cancers [56,57]. Moreover, a similar effect has been recently reported for the effect of dasatinib in the CIA model of arthritis [44].…”

Section: Discussionsupporting

confidence: 92%

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Ntari¹,

Nikolaou

Kranidioti³

et al. 2021

J Transl Med

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Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

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Section: Discussionsupporting

confidence: 92%

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Ntari¹,

Nikolaou

Kranidioti³

et al. 2021

J Transl Med

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show abstract

“…The most marked effect of dasatinib was observed in its ability to protect from cartilage destruction and bone erosion. These ndings are in line with previous reports supporting that dasatinib demonstrates convergent bone anabolic (29) and reduced bone resorption effects (29), osteoclast inhibitory functions (51), enhancement of chondrogenesis (52) as well as enhanced bone preservation in metastatic cancers (53,54). Moreover a similar effect has been recently reported for the effect of dasatinib in the CIA model of arthritis (41).…”

Section: Discussionsupporting

confidence: 92%

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Ntari¹,

Nikolaou

Kranidioti³

et al. 2020

Preprint

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Background Medications for Rheumatoid Arthritis (RA) have emerged in the last two decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-depended manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of this combination therapy may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

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“…Moreover, dasatinib promoted significantly higher relative gain and relative lower loss in the bone volume of xenografted mice. Collectively, these findings supported the fact that dasatinib prevented metastases of osteotropic MDA-MB-231 cells to the bone (55).…”

Section: Xenografted Mice Based Studiessupporting

confidence: 75%

“…Bone seeking MDA-MB-231-cancer cells were injected into the left ventricle of anesthetized mice (55). Intra-peritoneally administered dasatinib significantly reduced number of metastases.…”

Section: Xenografted Mice Based Studiesmentioning

confidence: 99%

TRAIL mediated signaling in different cancers: cancer in the "Crosshairs"

Farooqi

Naureen

Yılmaz

et al. 2020

Cell Mol Biol (Noisy-le-grand)

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Cancer is a therapeutically challenging disease because of its heterogeneous and multifaceted nature. Decades of research have sequentially and systematically enabled us to develop a sharper and better understanding of the heterogeneous nature of cancer. Genetic, genomic and proteomic studies have unraveled wide-ranging signaling cascades which play cornerstone role in disease onset and progression. More importantly, activation of pro-survival signaling and loss of apoptosis also play critical role in cancer progression. TRAIL-mediated signaling pathway has emerged as one of the most comprehensively analyzed cascade because of its exceptional ability to target cancer cells while leaving normal cells intact. TRAIL discovery and landmark achievements related to TRAIL/TRAIL-receptor signaling pathway attracted the attention of researchers. Therefore, scientists started to add missing pieces to an incomplete jig-saw puzzle and allowed contemporary researchers to conceptualize a better molecular snapshot of TRAIL-induced signaling in various cancers. Circumstantial evidence illuminated a functionally unique "push and pull" between anti-apoptotic and pro-apoptotic proteins in different cancers. Overexpression of anti-apoptotic proteins and inactivation of pro-apoptotic proteins shifted the balance towards loss of apoptosis. There has been a breakneck increase in the number of clinical trials related to TRAIL-based therapeutics which validate the true pharmacological potential of TRAIL-based therapeutics as effective anticancer agents. However, apart from advancements in our clinical understanding about the efficacy of TRAIL-based therapeutics, researchers have also faced setbacks in the field of translational medicine. Therefore, in this review, we have attempted to set spotlight on the most recent and landmark discoveries which have leveraged our understanding related to TRAIL-mediated signaling altogether to a new level.

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Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model

Cited by 11 publications

References 48 publications

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

TRAIL mediated signaling in different cancers: cancer in the "Crosshairs"

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