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CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells.
Mitobe, Yuta; Suzuki, Shuhei; Nakamura, Kazuki; Nakagawa-Saito, Yurika; Takenouchi, Senri; Togashi, Keita; Sugai, Asuka; Sonoda, Yukihiko; Kitanaka, Chifumi; Okada, Masashi.
Afiliación
  • Mitobe Y; Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Suzuki S; Department of Neurosurgery, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Nakamura K; Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Nakagawa-Saito Y; Department of Clinical Oncology, Yamagata Prefectural Shinjo Hospital, 720-1 Kanazawa, Shinjo, Yamagata 996-8585, Japan.
  • Takenouchi S; Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Togashi K; Department of Neurosurgery, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Sugai A; Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Sonoda Y; Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Kitanaka C; Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
  • Okada M; Department of Ophthalmology and Visual Sciences, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Int J Mol Sci ; 25(17)2024 Aug 30.
Article en En | MEDLINE | ID: mdl-39273420
ABSTRACT
Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Radiación Ionizante / Neoplasias Encefálicas / Proteína p53 Supresora de Tumor / Quinasa de Punto de Control 2 Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Suiza
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Radiación Ionizante / Neoplasias Encefálicas / Proteína p53 Supresora de Tumor / Quinasa de Punto de Control 2 Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Suiza