Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models.
Int J Oncol
; 46(4): 1801-9, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25672400
ABSTRACT
Multiple myeloma is a malignant proliferative disease of plasma cells in the bone marrow and remains largely incurable. Cotylenin A, a fusicoccane diterpene glycoside with a complex sugar moiety, was isolated as a plant-growth regulator. Cotylenin A has been shown to inhibit the growth of various cancer cells. Herein, we examined the anti-myeloma effects of cotylenin A using five human myeloma cell lines (RPMI-8226, KMS-11, KMS-26, KMS-12 PE and KMS-12 BM) and xenografts in immunodeficient mice. Cotylenin A and vincristine synergistically inhibited the growth and induced apoptosis in myeloma cells. While other microtubule-disturbing agents also showed co-operative effects with cotylenin A, other anticancer agents, such as doxorubicin, cisplatin, camptothecin, methotrexate, gemcitabine and 5-fluorouracil, did not show such co-operation with cotylenin A. These differences might be attributed to the effects on autophagic responses. Combined treatment with cotylenin A and vincristine induced autophagy (formation of LC3-II and degradation of p62 protein). However, doxorubicin did not enhance the autophagy induced by cotylenin A. A colony-forming assay indicated that the combined treatment with cotylenin A and vincristine more effectively suppressed the formation of large colonies, which have higher self-renewal activity than vincristine alone. Expression of pluripotency-associated transcription factor Sox2 mRNA in RPMI-8226 myeloma cells was significantly suppressed by treatment with cotylenin A. Combined treatment with cotylenin A and vincristine significantly inhibited the growth of KMS-26 myeloma cells as xenografts. Our results suggest that the combination of cotylenin A and vincristine may have therapeutic value. Recently, it was reported that cotylenin A modulates the 14-3-3 intracellular signaling pathway. The 14-3-3 proteins may be novel targets in treating myeloma. However, our study could not explain how the sensitization to vincristine is related to the effects of cotylenin A on the 14-3-3 signaling pathway and further studies will be needed.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Vincristina
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Protocolos de Quimioterapia Combinada Antineoplásica
/
Diterpenos
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Fatores de Transcrição SOXB1
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Mieloma Múltiplo
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Antineoplásicos Fitogênicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Int J Oncol
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Japão