Kadir, Mohamad F. A. and Othman, Shatrah and Nellore, Kavitha (2020) Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells. Current Pharmaceutical Biotechnology, 21 (15). pp. 1654-1665. ISSN 1389-2010, DOI https://doi.org/10.2174/1389201021666200611113734.
Full text not available from this repository.Abstract
Background: The re-emerging of targeting Dihydroorotate Dehydrogenase (DHODH) in cancer treatment particularly Acute Myelogenous Leukemia (AML) has corroborated the substantial role of DHODH in cancer and received the attention of many pharmaceutical industries. Objective: The effects of Brequinar Sodium (BQR) and 4SC-101 on lymphoblastoid cell lines were investigated. Methods: DHODH expression and cell proliferation inhibition of lymphoblastoid and lymphoma cell lines were analyzed using Western blot analysis and XTT assay, respectively. JC-1 probe and ATP biochemiluminescence kit were used to evaluate the mitochondrial membrane potential and ATP generation in these cell lines. Furthermore, we explored the cell cycle progression using Muse (TM) 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 of 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 a better therapeutic window in patients.
| Item Type: | Article |
|---|---|
| Funders: | Aurigene Discovery Technologies (M) Sdn. Bhd., Ministry of Education, Malaysia, Universiti Malaya (RP027D-15AFR), Universiti Malaya (PG038-2014A) |
| Uncontrolled Keywords: | Dihydroorotate dehydrogenase; ATP depletion; Mitochondrial membrane potential; S-phase arrest; Lymphoma; Brequinar sodium; 4SC-101 |
| Subjects: | Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology R Medicine R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 02 Jun 2023 02:31 |
| Last Modified: | 02 Jun 2023 02:31 |
| URI: | http://eprints.um.edu.my/id/eprint/37049 |
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