Itraconazole targets cell cycle heterogeneity in colorectal cancer.
J Exp Med
; 215(7): 1891-1912, 2018 07 02.
Article
em En
| MEDLINE
| ID: mdl-29853607
ABSTRACT
Cellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure after adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC), yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumor cells. Unexpectedly, we demonstrate that dormant CRC cells are differentiated, yet retain clonogenic capacity. Mouse organoid drug screening identifies that itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumor growth can also be perturbed by itraconazole, which is found to inhibit Wnt signaling through noncanonical hedgehog signaling. Preclinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide preclinical evidence to support an early phase trial of itraconazole in CRC.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Ciclo Celular
/
Itraconazol
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido