NEW YORK (Reuters Health) Feb 27 - Prior research has shown that the novel proteasome inhibitor NPI-0052 and histone deacetylase inhibitors (HDACi) are much more effective against leukemia when given together than either agent alone. Now, new research clarifies the mechanisms involved in the synergy. In short, it appears that NPI-0052 and HDACi share certain functions.
In an earlier study, Dr. Joya Chandra, from MD Anderson Cancer Center in Houston, and colleagues showed that the drugs synergistically induce apoptosis in leukemic cells through mechanisms dependent on caspase-8 activation and oxidative stress.
To further explore the mechanisms, the research team began by focusing on the proximal targets of NPI-0052 and HDACi, namely, blockage of proteasome activity and histone acetylation.
The new findings are reported in Blood, prepublished online on January 30.
NPI-0052 was found to have functions similar to HDACi. Alone or in combination with HDACi, NPI-0052 induced hyperacetylation in leukemic cells. This hyperacetylation was attenuated in cells lacking caspase-8 or those treated with an antioxidant. "These results indicate that NPI-0052 is eliciting caspase-8- and oxidative stress-dependent epigenetic alterations," the authors explain.
Likewise, HDACi were found to have functions of NPI-0052. One HDACi tested had repressed expression of proteasomal subunits.
"Our results suggest that crosstalk by NPI-0052 and HDACi are contributing, along with caspase-8 activation and oxidative stress, to their cytotoxic effects in leukemia cells, reinforcing the potential clinical utility of combining these two agents," the researchers conclude.
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