Novel ß-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer.
Cell Death Dis
; 9(9): 877, 2018 08 29.
Article
em En
| MEDLINE
| ID: mdl-30158525
ABSTRACT
Many stress conditions including chemotherapy treatment is known to activate Src and under certain condition Src can induce the apoptotic signal via c-Jun N-terminal kinase (JNK) activation. Here we report that the newly synthesized ß-phenylacrylic acid derivatives, MHY791 and MHY1036 (MHYs), bind to epidermal growth factor receptor (EGFR) tyrosine kinase domains and function as EGFR inhibitors, having anti-cancer activities selectively in wild-type KRAS colon cancer. Mechanistically, MHYs-induced Src/JNK activation which enhanced their pro-apoptotic effects and therefore inhibition of Src by the chemical inhibitor PP2 or Src siRNA abolished the response. In addition, MHYs generated reactive oxygen species and increased ER stress, and pretreatment with antioxidant-inhibited MHY-induced ER stress, Src activation, and apoptosis. Furthermore, the irreversible EGFR inhibitor PD168393 also activated Src while the reversible EGFR inhibitor gefitinib showed the opposite effect, indicating that MHYs are the irreversible EGFR inhibitor. Collectively, Src can play a key role in apoptosis induced by the novel EGFR inhibitor MHYs, suggesting that activation of Src might prove effective in treating EGFR/wild-type KRAS colon cancer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genes src
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Proteínas Proto-Oncogênicas p21(ras)
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Apoptose
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Neoplasias do Colo
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Quinases da Família src
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2018
Tipo de documento:
Article