Combinatory anti-tumor activities of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4) and temsirolimus against colorectal cancer cells.
J Cancer Res Clin Oncol
; 149(8): 4689-4699, 2023 Jul.
Article
en En
| MEDLINE
| ID: mdl-36220941
ABSTRACT
PURPOSE:
Banoxantrone is a topoisomerase II inhibitor that is selectively activated in hypoxia. Although it has exhibited anti-tumor activity against several types of cancers in preclinical models, its efficacy against colorectal cancer (CRC) remains unclear.METHODS:
We examined the antitumor effects of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4), an activated metabolite of banoxantrone, in CRC cell lines (HT-29, CaR-1) using in vitro experiments under normoxic and hypoxic conditions. The inhibition of cell growth was assessed using a proliferation assay. The induction of apoptosis and changes in the cell cycle were measured using flow cytometry. Signaling pathways involved in apoptosis and hypoxia were analyzed. The anti-tumor activity of temsirolimus, an inhibitor of mammalian target of rapamycin, and the combined effects of temsirolimus and AQ4 were also evaluated.RESULTS:
Regardless of the oxygen condition, a single drug treatment with AQ4 or temsirolimus inhibited proliferation and induced apoptosis in both cell lines, accompanied by a reduction in the phosphorylation of S6. AQ4 induced G2/M cell cycle arrest, whereas temsirolimus induced G0/G1 arrest. Moreover, the combined treatment markedly reduced the proportion of cells in the S phase and enhanced apoptosis, as evidenced by an increased Bax/Bcl-2 ratio. The hypoxia-induced activation of the HIF-1α pathway was suppressed by AQ4 and temsirolimus.CONCLUSION:
Based on the cooperative anti-tumor activity of AQ4 and temsirolimus in vitro, the combination of banoxantrone plus temsirolimus has potential as a treatment option for CRC in preclinical and clinical settings.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Hipoxia
Límite:
Humans
Idioma:
En
Revista:
J Cancer Res Clin Oncol
Año:
2023
Tipo del documento:
Article
País de afiliación:
Japón