Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors.
Anticancer Res
; 43(3): 1043-1052, 2023 Mar.
Article
em En
| MEDLINE
| ID: mdl-36854524
ABSTRACT
BACKGROUND/AIM:
MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed. MATERIALS ANDMETHODS:
To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells.RESULTS:
CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells.CONCLUSION:
CCL347 has potential as a novel therapeutic drug for HCC.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
/
Proteínas ADAM
/
Neoplasias Hepáticas
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
Anticancer Res
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Japão