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High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells
Diana Pádua1,2,3, Paula Figueira1,2, Mariana Pinto1,2
1i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal.
Abstract:
Cancer stem cells (CSCs) are relevant therapeutic targets for cancer treatment. Still, the molecular circuits behind CSC characteristics are not fully understood. The low number of CSCs can sometimes be an obstacle to carrying out assays that explore their properties. Thus, increasing CSC numbers via small molecule-mediated cellular reprogramming appears to be a valid alternative tool. Using the SORE6-GFP reporter system embedded in gastric non-CSCs (SORE6-), we performed a high-throughput image-based drug screen with 1200 small molecules to identify compounds capable of converting SORE6- to SORE6+ (CSCs). Here, we report that the antifungal agent ciclopirox olamine (CPX), a potential candidate for drug repurposing in cancer treatment, is able to reprogram gastric non-CSCs into cancer stem-like cells via activation of SOX2 expression and increased expression of C-MYC, HIF-1α, KLF4, and HMGA1. This reprogramming depends on the CPX concentration and treatment duration. CPX can also induce cellular senescence and the metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. We also disclose that the mechanism underlying the cellular reprogramming is similar to that of cobalt chloride (CoCl2), a hypoxia-mimetic agent.
Insights
The antifungal ciclopirox olamine (CPX) can reprogram gastric non-cancer stem cells (CSCs) into CSCs by activating SOX2. This drug repurposing candidate also induces senescence and metabolic shifts, offering new cancer treatment avenues.
Area of Science:
- Oncology
- Cell Biology
- Drug Discovery
Background:
- Cancer stem cells (CSCs) are crucial therapeutic targets, but their low numbers hinder research.
- Understanding CSC molecular circuits is key to developing effective cancer treatments.
- Small molecule-mediated cellular reprogramming offers a method to increase CSC numbers for study.
Purpose of the Study:
- To identify compounds capable of reprogramming gastric non-CSCs into CSCs.
- To investigate the molecular mechanisms underlying this reprogramming process.
- To explore the potential of drug repurposing for cancer stem cell generation.
Main Methods:
- A high-throughput image-based drug screen of 1200 small molecules using a SORE6-GFP reporter system in gastric non-CSCs.
- Assessing the effects of identified compounds on CSC marker expression (SOX2, C-MYC, HIF-1α, KLF4, HMGA1).
- Investigating CPX-induced cellular senescence, metabolic shifts (OXPHOS to glycolysis), and mechanism of action compared to cobalt chloride.
Main Results:
- Ciclopirox olamine (CPX) was identified as a compound that reprograms gastric non-CSCs to CSCs (SORE6+).
- CPX activates SOX2 expression and upregulates C-MYC, HIF-1α, KLF4, and HMGA1 in a dose- and time-dependent manner.
- CPX also induces cellular senescence and a metabolic shift from oxidative phosphorylation to glycolysis, with a mechanism similar to cobalt chloride.
Conclusions:
- Ciclopirox olamine (CPX) is a promising candidate for drug repurposing, capable of generating cancer stem-like cells from non-CSCs.
- The reprogramming mechanism involves SOX2 activation and is influenced by CPX concentration and duration.
- CPX's ability to induce senescence and alter cellular metabolism provides further insights into its therapeutic potential in cancer treatment.
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