ABT737 increases cisplatin sensitivity through the ROSASK1JNK MAPK signaling axis in human ovarian cancer cisplatinresistant A2780/DDP cells.
Oncol Rep
; 52(3)2024 09.
Article
em En
| MEDLINE
| ID: mdl-39054955
ABSTRACT
Ovarian cancer is a gynecological malignant tumor with the highest mortality rate, and chemotherapy resistance seriously affects patient therapeutic outcomes. It has been shown that the high expression of antiapoptotic proteins Bcl2 and BclxL is closely related to ovarian cancer chemotherapy resistance. Therefore, reducing Bcl2 and BclxL expression levels may be essential for reversing drug resistance in ovarian cancer. ABT737 is a BH3only protein mimetic, which can effectively inhibit the expression of the antiapoptotic proteins BclxL and Bcl2. Although it has been shown that ABT737 can increase the sensitivity of ovarian cancer cells to cisplatin, the specific molecular mechanism remains unclear and requires further investigation. In the present study, the results revealed that ABT737 can significantly increase the activation levels of JNK and ASK1 induced by cisplatin in A2780/DDP cells, which are cisplatinresistant ovarian cancer cells. Inhibition of the JNK and ASK1 pathway could significantly reduce cisplatin cytotoxicity increased by ABT737 in A2780/DDP cells, while inhibiting the ASK1 pathway could reduce JNK activation. In addition, it was further determined that ABT737 could increase reactive oxygen species (ROS) levels in A2780/DDP cells induced by cisplatin. Furthermore, the inhibition of ROS could significantly reduce JNK and ASK1 activation and ABT737mediated increased cisplatin cytotoxicity in A2780/DDP cells. Overall, the current data identified that activation of the ROSASK1JNK signaling axis plays an essential role in the ability of ABT737 to increase cisplatin sensitivity in A2780/DDP cells. Therefore, upregulation the ROSASK1JNK signaling axis is a potentially novel molecular mechanism by which ABT737 can enhance cisplatin sensitivity of ovarian cancer cells. In addition, the present research can also provide new therapeutic strategies and new therapeutic targets for patients with cisplatinresistant ovarian cancer with high Bcl2/BclxL expression patterns.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Piperazinas
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Sulfonamidas
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Compostos de Bifenilo
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Cisplatino
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Espécies Reativas de Oxigênio
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Resistencia a Medicamentos Antineoplásicos
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Sistema de Sinalização das MAP Quinases
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MAP Quinase Quinase Quinase 5
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Nitrofenóis
Limite:
Female
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Humans
Idioma:
En
Revista:
Oncol Rep
/
Oncol. rep
/
Oncology reports
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2024
Tipo de documento:
Article