MORPHOFUNCTIONAL STATE OF BLOOD CELLS AFTER CHRONIC EXPOSURE OF THE PROTEIN KINASES INHIBITOR MALEIMIDE DERIVATIVE
I.V. Byelinska, O.V. Lynchak, S.M.Tsyvinska, V.K. Rybalchenko
Taras Shevchenko National University of Kyiv
The effect of the protein kinases inhibitor maleimide derivative
( MI- 1, 1‑(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1Hpyrrole-2,5-dione),
inhibitor of VEGF‑R1,2,3, FGF-R1,
EGF‑R(h), PDK1, Src(h), Syk(h), YЕS, ZAP70 et al. with
antineoplastic activity, on blood cells parameters of rats after
chronic exposure has been studied. Administration of MI-1 at
doses 0.027 and 2.7 mg/kg (suppress colon carcinogenesis)
for 20 and 26 weeks does not affect the morphofunctional
state of red blood cells in healthy rats. This is confirmed by
the lack of differences in the concentration of hemoglobin in
blood, red blood cells count, mean corpuscular hemoglobin
and mean corpuscular hemoglobin concentration, hematocrit
and mean corpuscular volume, and the number of reticulocytes
in blood after 20 and 26 weeks of exposure compared with the
control group. MI-1 at indicated doses does not influence total
leukocytes count and content (eosinophilic and neutrophilic
granulocytes, lymphocytes, monocytes) and does not inhibit
thrombocytopoiesis (platelet count remains unchanged).
No negative effect of MI-1 on hematopoiesis is not limited (by
the hemopoietic system) use of this compound as a potential
maleimide derivative; protein kinases inhibitor; erythrocytes; leukocytes; platelets.
- Dubinina GG, Volovenko YuM. Compound of 1,4-disubstituted 5-amino-1,2-dihydropyrrole-3-one having anticancer activity. Pat. 22204 (UA). 21.02.2006. Appl. U200601855. 25.04.2007.
- Garmanchuk LV, Linchak OV, Niculina VV, Dzhus OI, Chranovskaya NN, Nicolaenko TV, Babuta EN, Rybalchenko VK. Potential cytostatic effect of the Maleimide derivative 1-(4-Sl-benzyl)-3-Cl-4-(CF3-phenylamino)- 1N-pyrrole-2,5-dione. Eksperim Klin Farmakol. 2013;76(8):39–42.
- Filinska OM, Yablonska SV, Mandryk SY, Kharchuk IV, Ostrovska GV, Rybalchenko VK. State of the liver antioxidant system and content of matrix metalloproteinase-2 of large intestine under the effect of maleimide derivative in experimental colon carcinogenesis in rats. Ukr Biochem J. 2010;82(4):69–77.
- Kharchuk IV, Filinska OM, Yablonska SV, Rybalchenko TV. The structure functional status of rat kidney and pancreas after the long-term influence of novel targeted-action compound - maleimide derivative. Reports of the National Academy of Sciences of Ukraine. 2010; 7:150–4.
- Kent D, Copley M, Benz C, Dykstra B, Bowie M, Eaves C. Regulation of Hematopoietic Stem Cells by the Steel Factor/KIT Signaling Pathway. Clin Cancer Res. 2008;14(7):1926–30.
- Rane SG, Reddy EP. JAKs, STATs and Src kinases in hematopoiesis. Oncogene. 2002;21:3334–58.
- Pearn L, Fisher J, Burnett AK, Darley RL. Theroleof PKC and PDK1 in monocyte lineage specification by Ras. Blood. 2007;109(10):4461–9.
- Byelinska IV, Rybalchenko VK, Ostrovska GV, Dyagil IS. Hematological effects of protein kinases inhibitor maleimide derivative (1–(4–Cl–benzyl)–3–Cl–4–(CF3– phenylamino)–1N–pyrrole–2,5–dione). J Pre–Clin and Clin Res. 2010;4(1):32–5.
- Byelinska IV, Lynchak OV, Rybalchenko TV, Gurnyak OM. Hematological effects of the protein kinases inhibitor maleimide derivative of dimethylhydrazineinduced colorectal carcinogenesis of rats. Fiziol Zh. 2014;60(4):40–9. [Ukrainian].
- Grzhibovskiy AM. Analysis of three or more independent groups of quantitative data. Ecology of human. 2008;(3):50–8. [Russian]
- Bone HK, Welham MJ. Phosphoinositide 3-kinase signalling regulates early development and developmental haemopoiesis. J Cell Science. 2007;120:1752–62.
- Yang KJ, Shin S, Piao L, Shin E, Li Y, Ah Park K, Byun HS, Won M, Hong J, Kweon GR, Hur GM, Seok JH, Chun T, Brazil DP, Hemmings BA, Park J. Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src SH2 domain binding. J Biol Chem. 2008;283:1480–91.
- Slavova-Azmanova NS, Kucera N, Satiaputra J, Stone L, Magno A, Maxwell MJ, Quilici C, Erber W, Klinken SP, Hibbs ML, Ingley E. Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling. Blood. 2013;122(2):262–71.
- Filinska OM, Yablonska SV, Mandryk SY, Kharchuk IV, Ostrovska GV, Rybalchenko VK. Changesin biochemical parameters of ratserum under the influence of maleimide derivative in colorectal cancerogenesis. Probl Ekologich and Med Genet and Clin Imunol. 2009;8(95):75–83. [Ukraine].
- Czepluch FS, Olieslagers S, van Hulten R, Vöö SA, Waltenberger J. VEGF-A-induced chemotaxis of CD16+ monocytes is decreased secondary to lower VEGFR-1 expression. Atherosclerosis. 2011;215(2):331–8.
- Vallières F, Girard D. IL-21 enhances phagocytosis in mononuclear phagocyte cells: identification of spleen tyrosine kinase as a novel molecular target of IL‑21. Immunol. 2013;190(6):P.2904–12.
- Byelinska I, Garmanchuk L, Andrushchenko O, Kalmykova O, Rybalchenko V. Morpho-frunctional state of cells line U-937 after the influence of protein kinase inhibitor - maleimide derivative. International Symposium on Cell Biology jointly with 4rd Ukrainian Congress of Cell Biology 17-20 September 2014. Uzhgorod, Ukraine. Abcstract book. 2014; P.113.
- Zeng Z, Samudio IS, Zhang W, Estrov Z, Pelicano H, Harris D, Frolova O, Hail N, Chen W, Kornblau SM, Huang P, Lu Y, Mills GM, Andreeff M, Konopleva M. Simultaneous Ingibition of PDK1/AKT and Fms-Like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and Apoptosis in Acute myelogeneous leukemia. Cancer Res. 2006; 66:3737–46.
- Carnevale J, Ross L, Puissant A, Banerji V, Stone RM, DeAngelo DJ, Ross KN, Stegmaier K. SYK Regulates mTOR Signaling in AML. Leukemia. 2013;27(11):2118– 28.
- Nakao T, Geddis AE, Fox NE, Kaushansky K. PI3K/ Akt/FOXO3a pathway contributes to thrombopoietininduced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27Kip1. Cell Cycle. 2008;7(2):257–66.