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Poster
88 |
The potential of Pim kinase as a candidate of target protein for new parasiticidal drug against Echinococcus multilocularis |
[Background]
The larval stage of Echinococcus multilocularis is the causative agent of alveolar echinococcosis. The standard chemotherapy for human echinococcosis is Albendazole, but its effect is parasitistatic rather than parasiticidal. Presumably because Albendazole does not affect germinative stem cells in the larval vesicles, lifelong medication is sometimes required to avoid relapses. Therefore, there is demand for the development of new parasiticidal drugs.
In human, proto oncogene serine / threonine protein kinases (Pim kinases) is a positive cell cycle regulator of the G2/M transition. One of known interaction partners of Pim1 is Cell division cycle 25c(Cdc25c). Pim1 phosphorylates Cdc25c, and activated Cdc25c transmits the signal for the initiation of the mitosis to downstream. Multiple anti-cancer drugs targeting Pim kinases have been developed, because their expression level is elevated in some type of cancers.
In Echinococcus multilocularis, germinative stem cells are the only proliferating cells. In Echinococcal genome, there is a gene which has high homology with human Pim kinases. According to the expression data, this Echinococcal Pim kinase seems to be expressed in stem cells.
[Methodology]
We applied yeast two-hybrid to clarify that there is interaction between Echinococcal Pim kinase and Echinococcal Cdc25c.
In addition, we tested multiple Pim kinase inhibitors including SGI-1776 and CX-6258, on larval vesicles and primary cells isolated from the vesicles in vitro. We evaluated the decrease of the cell viability of primary cells, how much vesicles are regenerated from primary cells, and how the structures of larval vesicles are altered by the treatment of inhibitors.
[Result and Discussion]
The result of yeast-two hybrid indicated that Echinococcal Pim kinase has interaction with Echinococcal Cdc25c. The same as human Pim1, Echinococcal Pim kinase is likely to regulate cell cycle progression through the activation of Echinococcal Cdc25c. We can expect that the inhibition of Echinococcal Pim kinase has some effect on the proliferation of germinative stem cells, and eventually has some effect on the survival or regeneration of larval vesicles.
In fact, one Pim kinase inhibitor, SGI-1776 showed strong detrimental effect on both larval vesicles and primary cells.
In conclusion, Echinococcal Pim kinase can be a good target of parasiticides and Pim kinase inhibitors can be promising lead compounds.
