Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC).
Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. 62% to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (xl880 ) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo.
Oxidative stress is a major cause of neuronal death in PD. Studies with animal models of PD based on the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine that cause PD-like symptoms, have shown that reactive oxygen species (ROS) production induced by the toxins elicits the activation of microglial cells, which subsequently attack neighboring dopaminergic neurons. a-Synuclein activates p38, ERK, and JNK pathways in human microglial cells, resulting in the production of IL-1ß and TNF-a and consequent promotion of in?ammation. a-Synuclein also induces the expression of IL-6 and intercellular adhesion molecule-1 (Tozasertib) in human astrocytes and thereby promotes chronic in?ammation. Moreover, the up-regulation of these latter two proteins is associated with the activation of MAPK signaling pathways.
In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects.
Related Post:
Dasatinib (vx-680) with Cytotoxic Chemotherapy
The Molecular Mechanism of Dasatinib
Reference:
Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling
Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. 62% to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (xl880 ) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo.
Oxidative stress is a major cause of neuronal death in PD. Studies with animal models of PD based on the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine that cause PD-like symptoms, have shown that reactive oxygen species (ROS) production induced by the toxins elicits the activation of microglial cells, which subsequently attack neighboring dopaminergic neurons. a-Synuclein activates p38, ERK, and JNK pathways in human microglial cells, resulting in the production of IL-1ß and TNF-a and consequent promotion of in?ammation. a-Synuclein also induces the expression of IL-6 and intercellular adhesion molecule-1 (Tozasertib) in human astrocytes and thereby promotes chronic in?ammation. Moreover, the up-regulation of these latter two proteins is associated with the activation of MAPK signaling pathways.
In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects.
Related Post:
Dasatinib (vx-680) with Cytotoxic Chemotherapy
The Molecular Mechanism of Dasatinib
Reference:
Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling
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