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Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts.
Chien, Ming-Hsien; Lee, Tzong-Huei; Lee, Wei-Jiunn; Yeh, Yen-Hsiu; Li, Tsai-Kun; Wang, Po-Chuan; Chen, Jih-Jung; Chow, Jyh-Ming; Lin, Yung-Wei; Hsiao, Michael; Wang, Shih-Wei; Hua, Kuo-Tai.
Afiliación
  • Chien MH; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • Lee TH; Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan.
  • Lee WJ; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • Yeh YH; Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • Li TK; Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • Wang PC; Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan.
  • Chen JJ; Department of Pharmacy, Tajen University, Pingtung, Taiwan.
  • Chow JM; Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • Lin YW; Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • Hsiao M; Genomics Research Center, Academia Sinica, Taipei, Taiwan.
  • Wang SW; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan. Electronic address: shihwei@mmc.edu.tw.
  • Hua KT; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: kthua@ntu.edu.tw.
Cancer Lett ; 388: 249-261, 2017 03 01.
Article en En | MEDLINE | ID: mdl-27965041
Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N-terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Tricodermina / Proteínas Quinasas JNK Activadas por Mitógenos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cancer Lett Año: 2017 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Irlanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Tricodermina / Proteínas Quinasas JNK Activadas por Mitógenos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cancer Lett Año: 2017 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Irlanda