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Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2

Dae Gyu Kim1, Chul Min Park2, Srigouri Huddar3,4

  • 1Medicinal Bioconvergence Research Center, College of Pharmacy and College of Medicine, Gangnam Severance hospital, Yonsei University, Incheon 21983, Korea.

Molecules (Basel, Switzerland)
|June 19, 2020
PubMed

Insights

Pyrimethamine effectively reduces lung cancer cells expressing high levels of the AIMP2-DX2 variant. This repurposed anti-parasite drug promotes DX2 degradation and inhibits tumor growth in vivo, suggesting potential for lung cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor.
  • Its splice variant, AIMP2-DX2, is upregulated in lung cancer, correlating with disease progression.

Purpose of the Study:

  • To investigate the potential of pyrimethamine as a repurposed drug for lung cancer.
  • To determine the effect of pyrimethamine on AIMP2-DX2 levels and lung cancer cell growth.

Main Methods:

  • Cell-based assays measuring DX2 levels and cell viability (IC50, GI50).
  • Immunoblotting to assess protein levels and ubiquitination.
  • In vivo mouse xenograft model to evaluate anti-tumor efficacy.

Main Results:

  • Pyrimethamine inhibited DX2 levels (IC50 = 0.73 µM) and suppressed H460 cell growth (GI50 = 0.01 µM).
  • The drug induced ubiquitination-mediated degradation of DX2 without affecting AIMP2.
  • In vivo, pyrimethamine significantly reduced tumor size and weight in mice, comparable to taxol.

Conclusions:

  • Pyrimethamine effectively targets and reduces AIMP2-DX2, a key molecule in lung cancer progression.
  • Repurposing pyrimethamine shows promise for treating lung cancer patients with high DX2 expression.
Keywords:
AIMP2-DX2anticancerdrug repositioningpyrimethamineubiquitination

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