Dihydroorotate dehydrogenase inhibitors may increase chemotherapy effectiveness in AML
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Dihydroorotate dehydrogenase inhibitors may increase the effectiveness of 3 + 7 chemotherapy and hypomethylating agents for acute myeloid leukemia, according to study results presented at Society of Hematologic Oncology Annual Meeting.
A deep pyrimidine starvation obtained through inhibition of both dihydroorotate dehydrogenase and the pyrimidine salvage pathway could further increase antileukemic activity, researchers wrote.
“The inhibition of dihydroorotate dehydrogenase was recently found to induce differentiation and apoptosis in AML,” Paola Circosta, PhD, postdoctoral researcher in the department of molecular biotechnology and health sciences at University of Turin in Italy, and colleagues wrote. “Multiple clinical trials testing dihydroorotate dehydrogenase inhibitors are currently ongoing, but the clinical effectiveness of these compounds is expected to be lower than in vitro due to the heterogeneity of the AML genetic landscape and the well-known ability of leukemic cells to undergo clonal escape when treated with single agents, and the pyrimidine salvage pathway, which could mitigate the pyrimidine starvation induced by dihydroorotate dehydrogenase inhibitors.”
Circosta and colleagues tested MEDS433, a dihydroorotate dehydrogenase inhibitor developed by the research group, on several AML cell line and primary cells alone and in combination with cytarabine, anthracyclines and decitabine.
AML cell lines tested included THP1, MV4-11, NB4, U937 and OCI-AML3.
Researchers also combined MEDS433 with dipyridamole, which inhibits the hENT1 and hENT2 nucleotide/nucleoside transport channels.
Increasing the apoptotic rate induced by dihydroorotate dehydrogenase inhibitors in AML cells served as the study objective.
Results showed adding MEDS433 to cytarabine, idarubicin and decitabine significantly increased the apoptotic rate in all AML cell lines tested.
Combining MEDS433 with dipyridamole led to a synergistic effect, with apoptotic rates ranging between 69% and 95% after 3 days of treatment at the lowest effective MEDS433 dose (0.1 µM). This, however, depended on the cell line.
Additionally, the combination of MEDS433, dipyridamole and chemotherapy resulted in the death of over 90% of AML cells.
“The addition of dihydroorotate dehydrogenase inhibitors to the 3 + 7 chemotherapy regimen or to hypomethylating agents could significantly increase the performances of these classical treatments,” Circosta and colleagues wrote. “Moreover, a deep pyrimidine starvation obtained through the inhibition of both dihydroorotate dehydrogenase and the pyrimidine salvage pathway could further increase the antileukemic activity. Ongoing in vivo experiments will be determinant to verify this hypothesis and to assess the toxicity on normal cells.”
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Circosta P, et al. Abstract AML-201. Presented at: Society of Hematologic Oncology Annual Meeting (virtual meeting); Sept. 9-12, 2020.
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