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Inhibition of triple­negative breast cancer proliferation and motility by reactivating p53 and inhibiting overactivated Akt.
Cao, Wei; Shen, Renhui; Richard, Seth; Liu, Yu; Jalalirad, Mohammad; Cleary, Margot P; D'Assoro, Antonio B; Gradilone, Sergio A; Yang, Da-Qing.
Afiliação
  • Cao W; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Shen R; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Richard S; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Liu Y; Sir Run Run Shaw Hospital, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
  • Jalalirad M; Mayo Clinic, Rochester, MN 55905, USA.
  • Cleary MP; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • D'Assoro AB; Mayo Clinic, Rochester, MN 55905, USA.
  • Gradilone SA; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
  • Yang DQ; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Oncol Rep ; 47(2)2022 02.
Article em En | MEDLINE | ID: mdl-34958116
Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple­negative breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, it was revealed that a specific inhibitor of histone deacetylase 6, ACY­1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggested that ACY­1215 may lead to enhanced transcriptional activity of p53. It was also determined that ACY­1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY­1215 displayed a synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, it was observed that combination of ACY­1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY­1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Proteína Supressora de Tumor p53 / Inibidores de Proteínas Quinases / Proliferação de Células / Proteínas Proto-Oncogênicas c-akt / Neoplasias de Mama Triplo Negativas / Proteínas Mutadas de Ataxia Telangiectasia / Ácidos Hidroxâmicos / Neoplasias Mamárias Experimentais Limite: Animals / Humans Idioma: En Revista: Oncol Rep Assunto da revista: NEOPLASIAS Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Proteína Supressora de Tumor p53 / Inibidores de Proteínas Quinases / Proliferação de Células / Proteínas Proto-Oncogênicas c-akt / Neoplasias de Mama Triplo Negativas / Proteínas Mutadas de Ataxia Telangiectasia / Ácidos Hidroxâmicos / Neoplasias Mamárias Experimentais Limite: Animals / Humans Idioma: En Revista: Oncol Rep Assunto da revista: NEOPLASIAS Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos