Dihydroorotate Dehydrogenase Inhibitors Promote Cell Cycle Arrest and Disrupt Mitochondria Bioenergetics in Ramos Cells

Kadir, Mohamad Fairus Abdul; Othman, Shatrah; Nellore, Kavitha

doi:10.2174/1389201021666200611113734

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…Dihydroorotate dehydrogenase (DHODH) is a key enzyme that catalyzes the rate-limiting step in pyrimidine biosynthesis. Vidofludimus is a DHODH inhibitor with potential anti-inflammatory, immunomodulating, and anti-viral activities, recently shown to promote cell cycle arrest in lymphoblastoid and lymphoma cell lines [ 34 ]. Although the MLL-AF9 harboring THP-1 and mAF9 cells showed limited sensitivity to Vidofludimus, recent reports suggest that second-generation DHODH inhibitors may have a particular role to play in MLL-AF9 AML and are now available at low concentrations (74 nM) with low toxicity [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

James

Curd

Ashworth

et al. 2023

IJMS

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In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an ‘early-stage’ model in which treatment was added shortly after initiation of AML cell encapsulation, and an ‘established’ model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the ‘established’ compared to the ‘early-stage’ model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs.

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Section: Discussionmentioning

confidence: 99%

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

James

Curd

Ashworth

et al. 2023

IJMS

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“…DUP785 (Brequinar) 0.56 Inhibits dihydroorotate dehydrogenase, thereby blocking de novo pyrimidine biosynthesis, [42] and disrupt mitochondria bioenergetics. [43] Rapamycin 0.56 See above.…”

Section: 76mentioning

confidence: 99%

Evaluation of Anticancer Activity of 1,3‐Oxazol‐4‐ylphosphonium Salts in Vitro

et al. 2022

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A novel series of 1,3-oxazol-4-yltriphenylphosphonium salts has been synthesized and functionalized. Oxazole derivatives were subjected to NCI in vitro assessment. Seven most active derivatives have been selected for five-dose assay. Among them, compounds 9 and 4 ( [5-phenyl-2-[(4methylphenyl)amino]-1,3-oxazol-4-yl]triphenylphosphonium perchlorate) were the most active against all tested cancer subpanels. Statistical analysis of the total panel data showed average values of parameters of anticancer activity in the range of 0.3-1.1 μM (GI 50 ), 1.2-2.5 μM (TGI) and 5-6 μM (LC 50 ). It was found that the presence of phenyl or 4-methylphenyl groups at C(2) and C(5) in the oxazole ring is of critical importance for the manifestation of the anticancer activity. Matrix COMPARE analysis using LC 50 vector showed a high positive correlation of compound 9 with standard anticancer agents that can directly disrupt mitochondrial function, causing programmed death of cancer cells. The obtained results indicate the anticancer activity of 1,3-oxazol-4-ylphosphonium salts, which could be useful for developing new anticancer drugs. The most active of them can be recommended for further in-depth studies and synthesis of new derivatives with antitumor activity on their basis.

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A Preliminary Study on the Impact of UCK2 Knockdown in DLD-1 Colorectal Cells Treated with DHODH Inhibitor

Kadir¹,

Abdul‐Rahman²,

Nellore³

et al. 2021

JSM

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Brequinar sodium (BQR) is a well-studied inhibitor of the dihydroorotate dehydrogenase (DHODH) enzyme. Both the DHODH and uridine-cytidine kinase 2 (UCK2) enzymes have been reported to be over-expressed in cancer cells to maintain the cells high demand for DNA and RNA for their proliferation. In this study, we aim to further sensitize cells to the effects of BQR by knocking down the UCK2 activity. In DLD-1 UCK2 knockdown cells, no change in the sensitivity of cells to BQR was observed. Uridine is known to reverse the anti-proliferative effect of DHODH inhibitors via the salvage pathway. We observed abrogation of approximately 30% of the uridine reversal effect in UCK2 knockdown cells compared to the wild type cells. Our finding indicates that the loss of UCK2 activity in the salvage pathway did not enhance the BQR-mediated cell proliferation inhibition but it abrogates the uridine reversal in the cells.

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Dihydroorotate Dehydrogenase Inhibitors Promote Cell Cycle Arrest and Disrupt Mitochondria Bioenergetics in Ramos Cells

Cited by 3 publications

References 52 publications

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

Evaluation of Anticancer Activity of 1,3‐Oxazol‐4‐ylphosphonium Salts in Vitro

A Preliminary Study on the Impact of UCK2 Knockdown in DLD-1 Colorectal Cells Treated with DHODH Inhibitor

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