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Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells

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 S...

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Main Authors: Kadir, Mohamad F. A., Othman, Shatrah, Nellore, Kavitha
Format: Article
Published: Bentham Science Publ Ltd 2020
Subjects:
QD Chemistry
QH301 Biology
R Medicine
RM Therapeutics. Pharmacology
Online Access:http://eprints.um.edu.my/37049/
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spelling my.um.eprints.370492023-06-02T02:31:09Z http://eprints.um.edu.my/37049/ Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells Kadir, Mohamad F. A. Othman, Shatrah Nellore, Kavitha QD Chemistry QH301 Biology R Medicine RM Therapeutics. Pharmacology 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. Bentham Science Publ Ltd 2020 Article PeerReviewed 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 <https://doi.org/10.2174/1389201021666200611113734>. 10.2174/1389201021666200611113734
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic QD Chemistry
QH301 Biology
R Medicine
RM Therapeutics. Pharmacology
spellingShingle QD Chemistry
QH301 Biology
R Medicine
RM Therapeutics. Pharmacology
Kadir, Mohamad F. A.
Othman, Shatrah
Nellore, Kavitha
Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells
description 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.
format Article
author Kadir, Mohamad F. A.
Othman, Shatrah
Nellore, Kavitha
author_facet Kadir, Mohamad F. A.
Othman, Shatrah
Nellore, Kavitha
author_sort Kadir, Mohamad F. A.
title Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells
title_short Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells
title_full Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells
title_fullStr Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells
title_full_unstemmed Dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in Ramos cells
title_sort dihydroorotate dehydrogenase inhibitors promote cell cycle arrest and disrupt mitochondria bioenergetics in ramos cells
publisher Bentham Science Publ Ltd
publishDate 2020
url http://eprints.um.edu.my/37049/
_version_ 1768007305226354688
score 13.211869

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