Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self-Renewal in Hepatocellular Carcinoma.
Target Oncol
; 12(4): 449-462, 2017 08.
Article
em En
| MEDLINE
| ID: mdl-28589491
ABSTRACT
BACKGROUND:
Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types.OBJECTIVE:
We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC.METHODS:
We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds.RESULTS:
Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5-fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo.CONCLUSIONS:
This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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Bibliotecas de Moléculas Pequenas
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Complexo Repressor Polycomb 1
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Neoplasias Hepáticas
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Target Oncol
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos