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Updated: Feb 28, 2026

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Pimozide Reprograms the Ran GTPase-SCF Axis and Matrix Remodeling Pathways in Breast, Colorectal, and Pancreatic

Hayat Asaad Hameed Al-Ali1, Mohammad El-Tanani2, Shakta Mani Satyam3

  • 1Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan.

Cancers
|February 27, 2026
PubMed
Abstract

Insights

Pimozide, an antipsychotic drug, shows anticancer effects by disrupting key cancer cell processes like transport and protein regulation. This drug repurposing offers a new multi-target strategy for cancer treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Cancer progression involves complex dysregulation of intracellular transport, proteostasis, and extracellular matrix remodeling.
  • Targeting single pathways often leads to tumor resistance, highlighting the need for multi-target agents.
  • Drug repurposing, using existing drugs like pimozide, offers a strategy for developing novel anticancer therapies with known safety profiles.

Purpose of the Study:

  • To investigate the anticancer effects of pimozide in breast, colorectal, and pancreatic cancer models.
  • To determine pimozide's impact on Ran GTPase signaling, Skp1-Cullin-F-box (SCF) ubiquitin ligase components, and matrix metalloproteinase-2 (MMP-2).

Main Methods:

  • Cell viability assessed via MTT assays in multiple cancer cell lines (MDA-MB-231, MCF-7, HT-29, PanC-1).
  • Gene expression analysis (quantitative real-time PCR) for key genes including Ran, MMP2, Cullin1, Rbx1, SKP2, and FBXW10.
  • Molecular docking and MMGBSA analyses to predict binding interactions between pimozide and target proteins.

Main Results:

  • Pimozide demonstrated concentration-dependent cytotoxicity across all tested cancer cell lines.
  • Consistent downregulation of Ran and MMP-2 observed, indicating disruption of nucleocytoplasmic transport and matrix remodeling.
  • In silico analyses revealed strong binding affinity of pimozide to FBXW10, suggesting interference with ubiquitin-mediated proteostasis.

Conclusions:

  • Pimozide exhibits anticancer properties by simultaneously affecting nucleocytoplasmic transport, proteostasis, and matrix remodeling.
  • These findings support the repositioning of pimozide as a potential multi-target anticancer agent.
  • The study provides a mechanistic basis for further clinical investigation of pimozide in cancer therapy.
Keywords:
FBXW10Ran GTPaseSCF ubiquitin ligasecancer signalingdrug repurposingmatrix metalloproteinase-2molecular dockingpimozideproteostasis

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