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

Pádua, Diana ; Figueira, Paula ; Pinto, Mariana ; Maia, André Filipe ; Peixoto, Joana ; Lima, Raquel T. ; Pombinho, António ; Pereira, Carlos Filipe LU orcid ; Almeida, Raquel and Mesquita, Patrícia (2023) In Cancers 15(17).
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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cancer stem cells, cellular reprogramming, cellular senescence, ciclopirox, cobalt chloride, gastric cancer, metabolic reprogramming, transcription factors
in
Cancers
volume
15
issue
17
article number
4406
publisher
MDPI AG
external identifiers
  • pmid:37686684
  • scopus:85170385158
ISSN
2072-6694
DOI
10.3390/cancers15174406
language
English
LU publication?
yes
id
6682af0a-3346-40a9-a215-83a71a72c33f
date added to LUP
2024-01-12 14:54:47
date last changed
2024-04-13 08:21:43
@article{6682af0a-3346-40a9-a215-83a71a72c33f,
  abstract     = {{<p>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 (CoCl<sub>2</sub>), a hypoxia-mimetic agent.</p>}},
  author       = {{Pádua, Diana and Figueira, Paula and Pinto, Mariana and Maia, André Filipe and Peixoto, Joana and Lima, Raquel T. and Pombinho, António and Pereira, Carlos Filipe and Almeida, Raquel and Mesquita, Patrícia}},
  issn         = {{2072-6694}},
  keywords     = {{cancer stem cells; cellular reprogramming; cellular senescence; ciclopirox; cobalt chloride; gastric cancer; metabolic reprogramming; transcription factors}},
  language     = {{eng}},
  number       = {{17}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells}},
  url          = {{http://dx.doi.org/10.3390/cancers15174406}},
  doi          = {{10.3390/cancers15174406}},
  volume       = {{15}},
  year         = {{2023}},
}