Acanthamoeba is
a ubiquitous and free-living protozoan
pathogen responsible for causing Acanthamoeba keratitis
(AK), a severe corneal infection inflicting immense pain that can
result in permanent blindness. A drug-based treatment of AK has remained
arduous because Acanthamoeba trophozoites undergo
encystment to become highly drug-resistant cysts upon exposure to
harsh environmental conditions such as amoebicidal agents (e.g., polyhexanide,
chloroquine, and chlorohexidine). As such, drugs that block the Acanthamoeba encystation process could result in a successful
AK treatment. Histone deacetylase inhibitors (HDACi) have recently
emerged as novel therapeutic options for treating various protozoan
and parasitic diseases. Here, we investigated whether novel HDACi
suppress the proliferation and encystation of Acanthamoeba. Synthetic class II HDACi FFK29 (IIa selective) and MPK576 (IIb
selective) dose-dependently decreased the viability of Acanthamoeba trophozoites. While these HDACi demonstrated a negligible effect
on the viability of mature cysts, Acanthamoeba encystation
was significantly inhibited by these HDACi. Apoptosis was slightly
increased in trophozoites after a treatment with these HDACi, whereas
cysts were unaffected by the HDACi exposure. The viability of human
corneal cells was not affected by HDACi concentrations up to 10 μmol/L.
In conclusion, these synthetic HDACi demonstrated potent amoebicidal
effects and inhibited the growth and encystation of Acanthamoeba, thus highlighting their enormous potential for further development.
The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased p21 expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs.
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