High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells

Author:

Pádua Diana123ORCID,Figueira Paula12,Pinto Mariana12,Maia André Filipe14ORCID,Peixoto Joana12ORCID,Lima Raquel T.125ORCID,Pombinho António14,Pereira Carlos Filipe678ORCID,Almeida Raquel1259,Mesquita Patrícia12ORCID

Affiliation:

1. i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal

2. IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal

3. ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal

4. IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal

5. Pathology Department, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

6. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal

7. Cell Reprogramming in Hematopoiesis and Immunity Laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden

8. Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden

9. Biology Department, Faculty of Sciences, University of Porto, 4169-007 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.

Funder

Norte Portugal Regional Operational Programme

Fundação para a Ciência e a Tecnologia

Programa Operacional Regional do Norte and European Regional Development Fund under the project “The Porto Comprehensive Cancer Center”

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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