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

TL;DR

Pimozide, a drug used for neurological disorders, may be repurposed to treat breast, colorectal, and pancreatic cancers by disrupting multiple cancer-related pathways.

Contribution

The study reveals pimozide's novel ability to simultaneously target multiple cancer-driving mechanisms across different cancer types.

Findings

Pimozide induces cytotoxicity in breast, colorectal, and pancreatic cancer cell lines.

Pimozide downregulates Ran and MMP-2 across cancer types and modulates SCF complex components.

FBXW10 shows the strongest binding affinity to pimozide, suggesting disruption of ubiquitin-mediated proteostasis.

Abstract

Cancer remains difficult to treat because tumors rely on multiple biological pathways to grow, spread, and resist therapy. Drugs that target only one pathway often fail due to resistance. Repurposing existing medicines offers a faster and safer way to discover new cancer treatments. Pimozide is a long-standing drug used for neurological disorders, but emerging evidence suggests it may also affect cancer-related processes. In this study, we investigated how pimozide influences key molecular systems that control protein transport, protein degradation, and tissue invasion in breast, colorectal, and pancreatic cancer cells. By combining laboratory experiments with computer-based molecular analysis, we show that pimozide disrupts several critical cancer-driving mechanisms simultaneously. These findings suggest that pimozide could be developed as a multi-target anticancer agent and provide new insights into how existing drugs may be redirected to treat aggressive cancers more effectively.

Background: Cancer progression is driven by coordinated dysregulation of intracellular transport, proteostasis, and extracellular matrix remodeling. Therapeutic strategies targeting a single pathway often fail due to tumor adaptability and resistance. Drug repurposing offers a promising approach to identify multi-target anticancer agents with established safety profiles. Pimozide, an FDA-approved antipsychotic drug, has recently emerged as a candidate with potential anticancer activity, although its molecular mechanisms remain incompletely understood. Objectives: This study aimed to investigate the anticancer effects of pimozide across breast, colorectal, and pancreatic cancer models, with a specific focus on its modulation of Ran GTPase signaling, Skp1–Cullin–F-box (SCF) ubiquitin ligase components, and matrix metalloproteinase-2–mediated extracellular matrix remodeling. Methods: Cell viability was assessed using MTT assays in MDA-MB-231, MCF-7, HT-29, and PanC-1 cell lines. Quantitative real-time polymerase chain reaction was employed to evaluate the expression of Ran, MMP2, Cullin1, Rbx1, SKP2, and FBXW10 following pimozide treatment. Molecular docking and MMGBSA analyses were performed to characterize binding interactions between pimozide and selected target proteins. Results: Pimozide induced concentration-dependent cytotoxicity in all tested cell lines with variable IC50 values. Treatment resulted in consistent downregulation of Ran and MMP-2 across cancer types, alongside context-dependent modulation of SCF complex components. Notably, FBXW10 exhibited the strongest binding affinity to pimozide in silico, suggesting functional disruption of ubiquitin-mediated proteostasis. Conclusions: Pimozide exerts anticancer effects through coordinated disruption of nucleocytoplasmic transport, proteostasis regulation, and matrix remodeling. These findings support the repositioning of pimozide as a multi-target anticancer agent and provide a mechanistic foundation for further translational investigation.

Figures