YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma.
Pharmacol Res
; 120: 242-251, 2017 Jun.
Article
em En
| MEDLINE
| ID: mdl-28396094
ABSTRACT
Primary effusion lymphoma (PEL) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for PEL. We screened 3518 compounds with known pharmaceutical activities based on cytotoxic effects on PDX cells of PEL and selected YM155, a possible survivin inhibitor. It exerted strong anti-tumor effects in PDX cells and three cell lines of PEL; the GI50 of YM155 was 1.2-7.9nM. We found that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein levels prior to decreasing survivin levels, and this was inhibited by a proteasome inhibitor. The knockdown of MCL-1 by siRNA induced cell death in a PEL cell line, suggesting the involvement of decreased MCL-1 levels in YM155-induced cell death. YM155 also induced the phosphorylation of ERK1/2 and MCL-1, and a MEK1 inhibitor inhibited the phosphorylation of ERK1/2, degradation of MCL-1, and YM155-induced apoptosis. These results indicate that YM155 induces the proteasome-dependent degradation of MCL-1 through its phosphorylation by ERK1/2 and causes apoptosis in PEL cells. Furthermore, a treatment with YM155 significantly inhibited the development of ascites in PEL PDX mice. These results suggest the potential of YM155 as an anti-cancer agent for PEL.
Palavras-chave
6-BIO (PubChem CID: 11405589); Chicago sky blue 6B (PubChem CID: 9566045); Daunorubicin (PubChem CID: 62770); Drug screening; HIV; Idarubicin (PubChem CID: 636362); Licochalcone A (PubChem CID: 5318998); Mitoxantrone (PubChem CID: 51082); Patient-derived xenograft; Phorbol 12-myristate 13-acetate (PubChem CID: 27924); Primary effusion lymphoma; Pyurvinium pamoate (PubChem CID: 7847555); Tomatine (PubChem CID: 23760126); U0126 (PubChem CID: 5354033); Valproic Acid Sodium Salt (PubChem CID: 24277744); Verteporfin (PubChem CID: 5362420); YM155; YM155 (PubChem CID: 11178236); Z-VAD-FMK (PubChem CID: 5497174)
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Naftoquinonas
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Apoptose
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Linfoma de Efusão Primária
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Proteólise
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Imidazóis
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Pharmacol Res
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Japão