DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells.
Cell Death Dis
; 8(5): e2810, 2017 05 25.
Article
em En
| MEDLINE
| ID: mdl-28542137
ABSTRACT
Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed malignant disease with the leading cause of cancer-related death. Combination treatment remains the major strategy in the clinical therapy of NSCLC. Vinorelbine (NVB), a semi-synthetic vinca alkaloid, is used for advanced and metastatic NSCLC by destabilizing microtubule formation to induce mitotic arrest and cell death. However, the side effect of NVB heavily affected its effectiveness in clinical therapy. Hence, it is of great significance to develop new agents to synergize with NVB and decrease the adverse effect. In our study, we found that the saponin monomer 13 of the dwarf lilyturf tuber, DT-13, exhibiting anti-angiogenesis and anti-metastasis effect, synergized with NVB to inhibit cell proliferation in NSCLC cells. The synergistic interaction of DT-13 and NVB was confirmed by combination Index values. Also, DT-13 and NVB act in concert to inhibit the long-term colony formation. Furthermore, DT-13/NVB co-treatment cooperated to induce mitotic arrest and subsequent apoptosis. Mechanistically, we found that nuclear expression of transcription factors forkhead box M1 (FOXM1) and levels of motor adaptor bicaudal D2 (BICD2) were dramatically reduced by combination treatment. Importantly, oncogene FOXM1 was identified as the crucial regulator of BICD2, which played critical roles in NVB-induced mitotic spindle defects. Moreover, overexpression of FOXM1 and BICD2 significantly reversed mitotic arrest induced by DT-13/NVB co-treatment, and siRNAs against both genes greatly increased the combinational effects. In addition, in vivo study revealed that DT-13 combined with NVB significantly suppressed tumor growth in nude mice xenograft model, and downregulated the expression of FOXM1 and BICD2 in tumor tissues, which was consistent with in vitro study. In conclusion, DT-13 might provide a novel strategy for the chemosensitization of NVB in NSCLC therapy.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Saponinas
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Vimblastina
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Carcinoma Pulmonar de Células não Pequenas
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Pontos de Checagem do Ciclo Celular
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Neoplasias Pulmonares
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Mitose
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2017
Tipo de documento:
Article