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  4. 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
 
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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

Journal
Cancer Letters
Journal Volume
388
Pages
249-261
Date Issued
2017
Author(s)
Chien, M.-H.
Lee T.-H.
Lee W.-J.
Yeh Y.-H.
TSAI-KUN LI  
Wang P.-C.
Chen J.-J.
Chow J.-M.
Lin Y.-W.
Hsiao M.
Wang S.-W.
TZONG-HUEI LEE et al.  
DOI
10.1016/j.canlet.2016.12.002
URI
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85007173843&doi=10.1016%2fj.canlet.2016.12.002&partnerID=40&md5=b5b6ce9b36eb5f02d5cb3a7324d58a08
https://scholars.lib.ntu.edu.tw/handle/123456789/597260
Abstract
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. ? 2016 Elsevier Ireland Ltd
SDGs

[SDGs]SDG3

Other Subjects
caspase; cyclin B1; cyclin dependent kinase 1; gemcitabine; protein p53; stress activated protein kinase; trichodermin; protein p53; stress activated protein kinase; trichodermin; animal experiment; animal model; animal tissue; antineoplastic activity; antiproliferative activity; apoptosis; Article; cancer inhibition; concentration response; controlled study; DNA damage; dose response; drug cytotoxicity; drug efficacy; drug mechanism; drug potency; enzyme activation; enzyme inhibition; epithelium cell; human; human cell; IC50; in vitro study; in vivo study; male; mitochondrial membrane potential; mitosis inhibition; mouse; nonhuman; pancreas cancer; pancreatic cancer cell line; priority journal; protein function; tumor xenograft; animal; antagonists and inhibitors; apoptosis; DNA damage; genetics; metabolism; mitosis; pancreas tumor; pathology; SCID mouse; signal transduction; tumor cell line; Animals; Apoptosis; Cell Line, Tumor; DNA Damage; Humans; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, SCID; Mitosis; Pancreatic Neoplasms; Signal Transduction; Trichodermin; Tumor Suppressor Protein p53
Publisher
Elsevier Ireland Ltd
Type
journal article

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