The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells.
cancer stem cells (CSCs)
combinational therapy
metabolic inhibitor
ovarian cancer chemoresistance
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
29 Oct 2019
29 Oct 2019
Historique:
received:
24
09
2019
revised:
18
10
2019
accepted:
23
10
2019
entrez:
2
11
2019
pubmed:
2
11
2019
medline:
2
11
2019
Statut:
epublish
Résumé
One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.
Identifiants
pubmed: 31671803
pii: cancers11111678
doi: 10.3390/cancers11111678
pmc: PMC6896080
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Advanced Medical Research Foundation
ID : N/A
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