| 研究概要 |
In order to precise the therapeutic effects of Limonoids, a novel type of inhibitors of sphingomyelin biosynthesis that we recently characterized, we analyzed their effects on various sphingolipid-dependent events. (1) Limonoid (Gedunin) pretreatment increased the toxicity of Doxorubicin on HeLa cells, but did not improve the efficiency of Paclitaxel treatment on other cancer cells such as A 549, Neuro 2A, or the toxicity of UV irradiation on HeLa cells, suggesting that modulation of sphingolipid metabolism can improve the efficiency of some types of anticancer treatment. (2) Limonoid (Gedunin) treatment of erythrocytes and HeLa cells inhibited, respectively, the growth of Plasmodium and Toxoplasma, 2 types of parasites whose growth is dependent of the sphingolipid content of the host cells. We previously reported that Limonoids favored the formation of ceramide-rich domains in the membrane. (3) We studied more in detail the formation and dynamics of these domains and especially the effect of Limonoids on the ceramide transbilayer movement using sulfhydryl analogues of ceramides synthetized in the laboratory. We succeeded to set up the experimental conditions in order to study the ceramide flip-flop in large and small unilamellar vesicles with different lipid composition mimicking that of different organelles (endoplasmic reticulum, Golgi, late endosomes, mitochondria ) implicated in sphingolipid metabolism and will try now the effect of Limonoids.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The first phase of the research project concerning the therapeutical effects of Limonoid treatment is progressing as expected since efficient modulation of sphingomyelin synthesis by some limonoids compounds could improve the treatment with anticancer drugs depending of the cellular models. Furthermore, the limonoid-induced decrease of sphingomyelin in the host cells seemed to limit the growth of parasites such as Plasmodium and Toxoplasma. In parallel, we started in vitro models to analyze the effect of Limonoids on ceramide dynamics in the membrane.
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| 今後の研究の推進方策 |
In the second phase of the project, we will study more in detail the secondary effects of the limonoid treatment on the cell growth of non-cancer cells (mimicking the surrounding tissue of a tumor) as well as on the host cells in the case of parasite infection. We will analyze the effect of Limonoids on the flip-flop or transbilayer movement of ceramides in liposome mimicking the lipid composition of different organelles (endoplasmic reticulum, Golgi, late endosomes, mitochondria ) since it is know that ceramide affects differently the membrane organization according to the surrounding lipids.
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