Dihydroorotate dehydrogenase inhibition acts synergistically with tyrosine kinase inhibitors to induce apoptosis of mantle cell lymphoma cells.

ABSTRACT: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the de novo biosynthesis of pyrimidine-based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely (R)-HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of (R)-HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre-clinical investigation on the efficacy of (R)-HZ05 shows t

SUBMITTER: Eriksen-Gjerstad M 

PROVIDER: S-EPMC9422018 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature