Synergism of a novel MCL1 downregulator, acriflavine, with navitoclax (ABT263) in triplenegative breast cancer, lung adenocarcinoma and glioblastoma multiforme.
Int J Oncol
; 60(1)2022 01.
Article
em En
| MEDLINE
| ID: mdl-34913076
ABSTRACT
Myeloid cell leukemia sequence 1 (MCL1), an antiapoptotic Bcell lymphoma 2 (BCL2) family molecule frequently amplified in various human cancer cells, is known to be critical for cancer cell survival. MCL1 has been recognized as a target molecule for cancer treatment. While various agents have emerged as potential MCL1 blockers, the present study presented acriflavine (ACF) as a novel MCL1 inhibitor in triplenegative breast cancer (TNBC). Further evaluation of its treatment potential on lung adenocarcinoma and glioblastoma multiforme (GBM) was also investigated. The anticancer effect of ACF on TNBC cells was demonstrated when MDAMB231 and HS578T cells were treated with ACF. ACF significantly induced typical intrinsic apoptosis in TNBCs in a dose and timedependent manner via MCL1 downregulation. MCL1 downregulation by ACF treatment was revealed at each phase of protein expression. Initially, transcriptional regulation via reverse transcriptionquantitative PCR was validated. Then, posttranslational regulation was explained by utilizing an inhibitor against protein biosynthesis and proteasome. Lastly, immunoprecipitation of ubiquitinated MCL1 confirmed the posttranslational downregulation of MCL1. In addition, the synergistic treatment efficacy of ACF with the wellknown MCL1 inhibitor ABT263 against the TNBC cells was explored [combination index (CI)<1]. Conjointly, the anticancer effect of ACF was assessed in GBM (U87, U251 and U343), and lung cancer (A549 and NCIH69) cell lines as well, using immunoblotting, cytotoxicity assay and FACS. The effect of the combination treatment using ACF and ABT263 was estimated in GBM (U87, U343 and U251), and nonsmall cell lung cancer (A549) cells likewise. The present study suggested a novel MCL1 inhibitory function of ACF and the synergistic antitumor effect with ABT263.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glioblastoma
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Neoplasias de Mama Triplo Negativas
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Adenocarcinoma de Pulmão
Limite:
Humans
Idioma:
En
Revista:
Int J Oncol
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2022
Tipo de documento:
Article