LAUSR

BACKGROUND The re-emerging of targeting dihydroorotate dehydrogenase (DHODH) in cancer treatment particularly acute myelogenous leukemia (AML) have corroborated the substantial role of DHODH in cancer and fascinated the attention of many pharmaceutical industries. OBJECTIVE The effects brequinar sodium (BQR) and 4SC-101 in lymphoblastoid cell lines were investigated. METHOD DHODH expression and cell proliferation inhibition of lymphoblastoid and lymphoma cell lines were analysed using Western blot analysis and XTT assay respectively. JC-1 probe and ATP biochemiluminescence kit was used to evaluate the mitochondrial membrane potential and ATP generation in these cell lines. Furthermore, we explored the cell cycle progression using Muse™ Cell Cycle Kit. RESULTS Ramos, SUDHL-1 and RPMI-1788 cells are fast-growing cells with equal expression of DHODH enzyme and sensitivity to DHODH inhibitors that showed that the inhibition of DHODH was not cancer specific. In ATP depletion assay, the non-cancerous RPMI-1788 cells showed only a minor ATP reduction compared to Ramos and SUDHL-1 (cancer) cells. In the mechanistic impact of DHODH inhibitors on non-cancerous vs cancerous cells, the mitochondrial membrane potential assay revealed that significant depolarization and cytochrome c release occurred with DHODH inhibitors treatment in Ramos but not in the RPMI-1788 cells, indicating a different mechanism of proliferation inhibition in normal cells. CONCLUSION The findings in this study provide evidence that DHODH inhibitors perturb the proliferation of non-cancerous cells via a distinct mechanism compared to cancerous cells. These results may lead to strategies for overcoming the impact on non-cancerous cells during treatment with DHODH inhibitors, leading to better therapeutic window in patients.