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

Mohamad F A Kadir1, Shatrah Othman1, Kavitha Nellore2

  • 1Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Current Pharmaceutical Biotechnology
|June 12, 2020
PubMed
Abstract

Insights

Dihydroorotate Dehydrogenase (DHODH) inhibitors impact cancer and non-cancer cells differently. Cancer cells show significant mitochondrial changes, while normal cells exhibit distinct proliferation inhibition mechanisms, suggesting targeted therapeutic strategies.

Area of Science:

  • Oncology
  • Biochemistry

Background:

  • Targeting Dihydroorotate Dehydrogenase (DHODH) is a key strategy in Acute Myelogenous Leukemia (AML) treatment.
  • DHODH's role in cancer has garnered significant pharmaceutical interest.

Purpose of the Study:

  • Investigate the effects of Brequinar Sodium (BQR) and 4SC-101 on lymphoblastoid cell lines.
  • Analyze DHODH expression and its impact on cell proliferation in cancerous and non-cancerous cells.

Main Methods:

  • Western blot for DHODH expression.
  • XTT assay for cell proliferation inhibition.
  • JC-1 probe and ATP assay for mitochondrial function.
  • Muse™ Cell Cycle Kit for cell cycle analysis.

Main Results:

  • DHODH inhibition affected both cancerous (Ramos, SUDHL-1) and non-cancerous (RPMI-1788) cells.
  • Cancer cells (Ramos) showed significant mitochondrial depolarization and cytochrome c release upon DHODH inhibition, unlike non-cancerous cells.
  • Non-cancerous cells exhibited a different mechanism of proliferation inhibition compared to cancer cells.

Conclusions:

  • DHODH inhibitors affect non-cancerous cell proliferation through a mechanism distinct from that in cancerous cells.
  • Findings suggest potential strategies to mitigate side effects on normal cells, improving the therapeutic window for DHODH inhibitor treatments.
Keywords:
4SC-101ATP depletionDihydroorotate dehydrogenaseS-phase arrestbrequinar sodiumlymphomamitochondrial membrane potential

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