Dasatinib monohydrate

Biochem J. 2015 Jan 15;465(2):271-9.

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases.[Pubmed: 25351958]

We demonstrate that the clinically approved cancer drugs bosutinib and Dasatinib monohydrate induce several hallmark features of 'regulatory'-like macrophages.
METHODS AND RESULTS:
Treatment of macrophages with bosutinib or Dasatinib monohydrate elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor α (TNFα) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or Dasatinib monohydrate express higher levels of markers of 'regulatory'-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and Dasatinib monohydrate were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and Dasatinib monohydrate on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and Dasatinib monohydrate induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and Dasatinib monohydrate on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2).
CONCLUSIONS:
In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and Dasatinib monohydrate that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.

Mol Med Rep. 2015 Sep;12(3):3249-56.

Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling.[Pubmed: 25975261]

The potential effect of Dasatinib monohydrate on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of Dasatinib monohydrate, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo.
METHODS AND RESULTS:
In the present study, the expression of Src and phospho‑Src-Y416 (p‑Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V‑fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of Dasatinib monohydrate alone and in combination with paclitaxel in ovarian cancer. High levels of p‑Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p‑Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib monohydrate treatment demonstrated anti‑ovarian cancer properties, by downregulating p‑Src expression and by inducing cancer cell apoptosis. Combined treatment with Dasatinib monohydrate and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined Dasatinib monohydrate and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25‑0.93 and 0.31‑0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone.
CONCLUSIONS:
Dasatinib monohydrate monotherapy demonstrated anti‑ovarian cancer activities. The effects of Dasatinib monohydrate and paclitaxel treatments on ovarian cancer cells appeared to be mediated by the Src pathway.

Cancer Lett. 2015 May 28;361(1):137-46.

Bortezomib enhances the therapeutic efficacy of dasatinib by promoting c-KIT internalization-induced apoptosis in gastrointestinal stromal tumor cells.[Pubmed: 25737303]

Dasatinib monohydrate-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of Dasatinib monohydrate target proteins, such as c-KIT and PDGFRβ, attenuates the therapeutic efficiency of Dasatinib monohydrate.
METHODS AND RESULTS:
Combination therapy which inhibits the activation of Dasatinib monohydrate target proteins may enhance the cytotoxicity of Dasatinib monohydrate in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of Dasatinib monohydrate-treated GIST-T1 cells, whereas GIST-T1 cells showed little Dasatinib monohydrate cytotoxicity when treated with Dasatinib monohydrate alone, as the upregulation of c-KIT caused by Dasatinib monohydrate itself interfered with the inhibition of c-KIT and PDGFRβ phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf-1, which was originally bound to the c-KIT-Hsp90β-Apaf-1 complex, induced primary apoptosis in GIST-T1 cells. Combined treatment with bortezomib plus Dasatinib monohydrate caused cell cycle arrest in the G1 phase through inactivation of PDGFRβ and promoted bortezomib-induced apoptosis in GIST-T1 cells.
CONCLUSIONS:
Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs.

Immunopharmacol Immunotoxicol. 2015 Jun;37(3):287-94.

Therapeutic effects of dasatinib in mouse model of multiple sclerosis.[Pubmed: 25975582]

Dasatinib monohydrate (Sprycel) is a selective protein tyrosine kinase inhibitor with immunomodulatory properties that abrogates multiple signal transduction pathways in immune cells. In the present research, our aim was to test the therapeutic efficacy of Dasatinib monohydrate in experimental model of MS.
METHODS AND RESULTS:
We performed EAE induction in female C57BL/6 mice by myelin oligodendrocyte glycoprotein35-55 (MOG35-55) in Complete Freund's Adjuvant (CFA) emulsion, and used Dasatinib monohydrate for the treatment of EAE. During the course of study, clinical evaluation was assessed, and on day 21 post-immunization blood samples were taken from the heart of mice for tumor necrosis factor-alpha (TNF-α), nitric oxide (NO) and antioxidants capacity evaluation. The mice were sacrificed and brains and cerebellums of mice were removed for histological analysis. Also for in vitro analysis, we used C6 astrocytoma cell line to evaluate the inhibitory effects of Dasatinib monohydrate in cell proliferation and matrix metalloproteinase-2 (MMP-2) activity. Our findings demonstrated that Dasatinib monohydrate had beneficial effects on EAE by lower incidence, attenuation in the severity and a delay in the onset of disease. The serum level of NO and TNF-α in Dasatinib monohydrate treated mice was significantly lower than control mice. In vitro, Dasatinib monohydrate inhibited cell proliferation and MMP-2 activity.
CONCLUSIONS:
Dasatinib monohydrate with its potential therapeutic effects and immunomodulatory properties may be recommended, after additional necessary tests and trials, for the treatment of MS.