TYROSINE KINASE INHIBITORS AGAINST HER4-LIKE PROTEIN OF TOXOPLASMA GONDII INHIBIT THE GROWTH IN ARPE-19 CELLS

초록

Toxoplasma gondii is a ubiquitous obligate intracellular parasite, which infects warm-blooded animals, including humans; it is a zoonotic pathogen widespread in nature. Approximately one-third of humans worldwide are chronically infected with T. gondii. To find a new drug for the treatment of toxoplasmosis, small molecules of tyrosine kinase inhibitor (TKI) against various kinds of growth factor receptors were tested the effect on the intracellular growth of T. gondii in the retinal cell line, ARPE-19. By counting the average number of tachyzoites per parasitophorous vacuole (PV) after treatment with TKIs, Nintedanib (blocks VEGFR1/2/3, PGFR1/2/3, PDGFRalpha/beta), AZD9291 (mutant EGFR), and Sunitinib (VEGFR2 and PDGFRbeta) did not affect the intracellular growth of tachyzoites up to the concentration of 10 microM, half the conc. of which destructed the host cell morphologically. On the while, the EGFR blocking TKIs, such as Lapatinib, Gefitinib, Erlotinib, AG-1478, Neratinib, Dacomitinib, Afatinib, and Pelitinib affected to inhibit the intracellular growth of tachyzoites of its own permissive conc. under the conc. of cytotoxicity. But for the former four TKIs which block the HER2 of EGFR family showed weak inhibitory effect with the treating conc. of 20, 30, 50, and 20-30 microM near to the conc. of cytotoxicity, whereas the latter four which block both HER2 and HER4 of EGFR family showed strong inhibitory effect with lower conc. of 0.5, 5, 5, and 5 microM. This suggests that those TKIs directly affect on the T. gondii molecule to inhibit the intracellular growth and that the target may be HER4-like protein of T. gondii.