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Information × Registration Number 0213U003130, 0110U000153 , R & D reports Title The study of signaling mechanisms of apoptosis induction of malignant cells during starvation for arginine and development of combined antitumor enzymotherapy methods on in vitro models popup.stage_title Head Stasyk O.V., Кандидат біологічних наук Registration Date 24-01-2013 Organization Institute of cell biology, National Academy of Sciences of Ukraine popup.description2 Methodical approaches to the cultivation of malignant cells in the form of 3-dimensional (3-D) spheroid cultures was designed, a comparative analysis of the impact of starvation on individual amino acids (arginine, leucine, lysine and methionine) on the growth and viability of tumor cells under conditions of its cultivation in 2- (2-D) and 3-dimensional cultures as well as a number of studies aimed at establishing the role of cell cycle regulation and mTOR-mediated signaling pathway in the response of tumor cells to starvation for arginine were executed. It has been shown for the first time that under cultivation in the form of 3-D spheroid malignant cells are more resistant to the action of arginine deficit as well as leucine, lysine and methionine, compared with 2-D monolayer cultures of these cells. Tumor cells, with constitutive activation of antiapoptotic PI3K-mTOR-Akt/PKB pathway and positive for p53, are resistant to starvation for arginine and other essential amino acids in monolayer culture, and vice versa. It is shown that the inability of tumor cells to stop in G1 phase of the cell cycle under conditions of starvation for arginine may be one of the reasons of their sensitivity to deficiency of this amino acid. In most cases, this property is correlated with damage of p53. It was found that starvation for arginine leads to significant changes in cell morphology and specific reduction in motility of tumor cells, regardless of their degree of sensitivity to arginine deficiency. The reason for this phenomenon may be changes in the organization of the cytoskeleton. It is shown that the use of an analogue of arginine of plant origin canavanine in medium without arginine or in combination with recombinant arginase leads to a selective decrease in viability and proliferative potential of epithelial human tumor cells of different organ origin, and slightly affects the survival of pseudonormal cells. Toxic antitumor effect of canavanine depends on protein synthesis de novo. It was established that suspension cells of human leukemias are especially sensitive to combination therapy based on starvation by arginine and canavanine and die by apoptosis under conditions in vitro. It is also shown that incubation in medium without arginine with canavanine leads not only to stop the growth of spheroid tumor cells, as in the case only starvation for arginine, but also to their partial disintegration. As in monolayer culture, canavanine selectively enhances caspase-dependent apoptosis induced by starvation for arginine in tumor cells in 3-D spheroid culture. Product Description popup.authors Ігуменцева Н.І. Барська М.Л. Бобак Я.П. Винницька-Мироновська Б.О. Вовк О.І. Воробець З.Д., Гриджук О.С. Данилейченко В.В. Денега І.О. Красовська О.С. Курліщук Ю.В. Линів Л.С. Маєвська О.М. Пєрєвєрзєва Г.Г. Ржепецький Ю.А. Сибірна Н.О. Стасик О.Г. Чень О.І. Чернишук С.В. Шуваєва Г.Ю. popup.nrat_date 2020-04-02 Close