Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.

• MeSH
• antitumorózní látky aplikace a dávkování   chemie   toxicita   MeSH
• aplikace intravezikální MeSH
• králíci MeSH
• kyselina olejová aplikace a dávkování   chemie   toxicita   MeSH
• laktalbumin aplikace a dávkování   chemie   toxicita   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• močový měchýř účinky léků   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie transplantace   MeSH
• nádory močového měchýře farmakoterapie   patologie   MeSH
• testy subchronické toxicity MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1-5min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky kostní dřeně účinky léků   MeSH
• extracelulárním signálem regulované MAP kinasy genetika   MeSH
• faktory stimulující kolonie genetika   MeSH
• fosfatidylinositol-3-kinasy genetika   MeSH
• kyselina olejová aplikace a dávkování   chemie   MeSH
• makrofágy účinky léků   MeSH
• MAP kinasový signální systém účinky léků   MeSH
• myši MeSH
• oxid dusnatý aplikace a dávkování   chemie   MeSH
• RAW 264.7 buňky MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• transkripční faktor STAT5 genetika   MeSH
• zánět farmakoterapie   genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH