4.6 Article

The Mitochondria-Independent Cytotoxic Effect of Leflunomide on RPMI-8226 Multiple Myeloma Cell Line

Journal

MOLECULES
Volume 26, Issue 18, Pages -

Publisher

MDPI
DOI: 10.3390/molecules26185653

Keywords

leflunomide; teriflunomide; multiple myeloma; dehydrogenase dihydroorotate; protein tyrosine kinases; mitochondria

Funding

  1. Medical University of Lublin [PBmb10]

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Leflunomide has been shown to have cytotoxicity against RPMI 8226 cell line in a DHODH- and mitochondria-independent mechanism. Teriflunomide, an active metabolite of leflunomide, induces G2/M phase cell cycle arrest and apoptosis in a mitochondria-independent manner, suggesting a unique cytotoxic mechanism. Moreover, teriflunomide does not affect cellular thiol levels, indicating a distinct pathway of toxicity.
Leflunomide, an anti-inflammatory agent, has been shown to be effective in multiple myeloma (MM) treatment; however, the mechanism of this phenomenon has not been fully elucidated. The aim of the study was to assess the role of mitochondria and dihydroorotate dehydrogenase (DHODH) inhibition in the cytotoxicity of leflunomide in relation to the MM cell line RPMI 8226. The cytotoxic effect of teriflunomide-an active metabolite of leflunomide-was determined using MTT assay, apoptosis detection, and cell cycle analysis. To evaluate DHODH-dependent toxicity, the cultures treated with teriflunomide were supplemented with uridine. Additionally, the level of cellular thiols as oxidative stress symptom was measured as well as mitochondrial membrane potential and protein tyrosine kinases (PTK) activity. The localization of the compound in cell compartments was examined using HPLC method. Teriflunomide cytotoxicity was not abolished in uridine presence. Observed apoptosis occurred in a mitochondria-independent manner, there was also no decrease in cellular thiols level. Teriflunomide arrested cell cycle in the G2/M phase which is not typical for DHODH deficiency. PTK activity was decreased only at the highest drug concentration. Interestingly, teriflunomide was not detected in the mitochondria. The aforementioned results indicate DHODH- and mitochondria-independent mechanism of leflunomide toxicity against RPMI 8226 cell line.

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