Suppression of systemic inflammation and signs of acute and chronic cholangitis by multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione

Q3 · BIOLOGY

Article

Author: Khilya, Olga ; Dziubenko, Natalia ; Klyuchivska, Olga ; Rybalchenko, Volodymyr ; Stoika, Rostyslav ; Finiuk, Nataliya ; Lynchak, Oksana ; Byelinska, Iryna ; Milokhov, Demyd ; Kuznietsova, Halyna

An aberrant activity of growth factor receptors followed by excessive cell proliferation plays a significant role in pathogenesis of cholangitis. Therefore, inhibition of these processes could be a fruitful therapeutic strategy. The effects of multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione (MI-1) on the hepatic and systemic manifestations of acute and chronic cholangitis in rats were addressed. MI-1 (2.7 mg/kg per day) was applied to male rats that experienced α-naphthylisothiocyanate-induced acute (3 days) or chronic (28 days) cholangitis. Liver autopsy samples, blood serum markers, and leukograms were studied. MI-1 localization in liver cells and its impact on viability of HepG2 (human hepatoma), HL60 (human leukemia), and NIH3T3 (normal murine fibroblasts) cell lines and lymphocytes of human peripheral blood (MTT, DNA fragmentation, DNA comet assays, Propidium Iodide staining) were assessed. Under both acute and chronic cholangitis, MI-1 substantially reduced liver injury, fibrosis, and inflammatory scores (by 46-86%) and normalized blood serum markers and leukograms. Moreover, these effects were preserved after a 28-day recovery period (without any treatment). MI-1 inhibited the HL60, HepG2 cells, and human lymphocytes viability (IC₅₀ 0.6, 9.5 and 8.3 µg/ml, respectively), while NIH3T3 cells were resistant to that. Additionally, HepG2 cells and lymphocytes being incubated with MI-1 demonstrated insignificant pro-apoptotic and pro-necrotic changes and DNA single-strand breaks, suggesting that MI-1 effects in liver might be partly caused by its cytotoxic action towards liver cells and lymphocytes. In conclusion, MI-1 attenuated the systemic inflammation and signs of acute and chronic cholangitis partly through cytotoxicity towards cells of hepatic and leukocytic origin.

01 Jul 2020·Human CellQ3 · BIOLOGY

Kasumi leukemia cell lines: characterization of tumor genomes with ethnic origin and scales of genomic alterations

Q3 · BIOLOGY

Article

Author: Kawamura, Machiko ; Ozawa, Midori ; Asou, Hiroya ; Kasai, Fumio ; Kohara, Arihiro ; Kuramitsu, Hiroyuki ; Kaneko, Yasuhiko ; Kobayashi, Kazuhiko ; Satoh, Motonobu

AbstractKasumi-1 has played an important role in an experimental model with t(8;21) translocation, which is a representative example of leukemia cell lines. However, previous studies using Kasumi-1 show discrepancies in the genome profile. The wide use of leukemia cell lines is limited to lines that are well-characterized. The use of additional cell lines extends research to various types of leukemia, and to further explore leukemia pathogenesis, which can be achieved by uncovering the fundamental features of each cell line with accurate data. In this study, ten Kasumi cell lines established in Japan, including five that were previously unknown, have been characterized by SNP microarray and targeted sequencing. SNP genotyping suggested that the genetic ancestry in four of the ten Kasumi cell lines was not classified as Japanese but covered several different east-Asian ethnicities, suggesting that patients in Japan are genetically diverse. TP53 mutations were detected in two cell lines with complex array profiles, indicating chromosomal instability (CIN). A quantitative assessment of tumor genomes at the chromosomal level was newly introduced to reveal total DNA sizes and Scales of Genomic Alterations (SGA) for each cell line. Kasumi-1 and 6 derived from relapsed phases demonstrated high levels of SGA, implying that the level of SGA would reflect on the tumor progression and could serve as an index of CIN. Our results extend the leukemia cellular resources with an additional five cell lines and provide reference genome data with ethnic identities for the ten Kasumi cell lines.

27 May 2020·Journal of Drug TargetingQ3 · MEDICINE

Pyrrole derivatives as potential anti-cancer therapeutics: synthesis, mechanisms of action, safety

Q3 · MEDICINE

Article

Author: Khilya, Olga ; Dziubenko, Natalia ; Byelinska, Iryna ; Hurmach, Vasyl ; Lynchak, Oksana ; Bychko, Andriy ; Milokhov, Demyd ; Rybalchenko, Volodymyr ; Kuznietsova, Halyna

Pyrrole derivatives (PDs) chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)amino)-1H-pyrrole-2,5-dione (MI-1) and 5-amino-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrole-3-one (D1) were synthesised as inhibitors of several protein kinases including EGFR and VEGFR. The aim of the study was to reveal the exact mechanisms of PDs' action EGFR and VEGFR are involved in. We observed, that both PDs could bind with EGFR and VEGFR and form stable complexes. PDs entered into electrostatic interactions with polar groups of phospholipid heads in cell membrane, and the power of interaction depended on the nature of PD radical substituents (greater for MI-1 and smaller for D1). Partial intercalation of MI-1 into the membrane hydrophobic zone also occurred. PDs concentrations induced apoptosis in malignant cells but normal ones had different sensitivity to those. MI-1 and D1 acted like antioxidants in inflamed colonic tissue, as evidenced by reduce of lipid and protein peroxidation products (by 43-67%) and increase of superoxide dismutase activity (by 40 and 58%) with restoring these values to control ones. MI-1 restored reduced haemoglobin and normalised elevated platelets and monocytes in settings of colorectal cancer, whereas D1 normalised only platelets. Thus, MI-1 and D1 could be used as competitive inhibitors of EGFR and VEGFR and antioxidants, which might contribute to realisation of their anti-inflammatory, proapoptotic and antitumor activity.

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Infarction	Discovery	AU	The University of Western Australia	-

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