Discovery and Characterization of 4-Hydroxy-2-pyridone Derivative Sambutoxin as a Potent and Promising Anticancer Drug Candidate: Activity and Molecular Mechanism
Autor: | Xiu-Li Guo, Xin-Ke Zhang, Yan-Na Cheng, Lu-Ning Li, Zhan-Qi Cao, Lei Wang |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cell cycle checkpoint DNA damage Pyridines Pharmaceutical Science Mice Nude Antineoplastic Agents Apoptosis 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Neoplasms Drug Discovery Animals Humans Viability assay Cyclin B1 Cell Proliferation chemistry.chemical_classification Cyclin-dependent kinase 1 Reactive oxygen species Mice Inbred BALB C Basidiomycota Mycotoxins Xenograft Model Antitumor Assays Cell biology G2 Phase Cell Cycle Checkpoints 030104 developmental biology Treatment Outcome chemistry 030220 oncology & carcinogenesis Cancer cell Molecular Medicine DNA Damage Signal Transduction |
Zdroj: | Molecular pharmaceutics. 15(11) |
ISSN: | 1543-8392 |
Popis: | Sambutoxin, a representative derivative of 4-hydroxy-2-pyridone, was isolated from Hericium alpestre for the first time in this study. The possible correlation between the sambutoxin-induced suppression of tumor growth and its influence on cell-cycle arrest and apoptosis was investigated. The effects of sambutoxin on reactive oxygen species (ROS) production, DNA damage, mitochondrial transmembrane potential, cell apoptosis, and the expression of related proteins were evaluated. An in vitro cell viability study demonstrated that sambutoxin could inhibit the proliferation of various cancer cells. Treatment with sambutoxin induced the production of ROS, which caused DNA damage. Furthermore, the subsequent sambutoxin-induced activation of ATM and Chk2 resulted in G2/M arrest, accompanied by decreased expression of cdc25C, cdc2, and cyclin B1. Sambutoxin induced apoptosis by activating the mitochondrial apoptosis pathway through an increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (ΔΨm), cytochrome (Cyt) c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) degradation. The ROS elevation induced the sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, a JNK inhibitor, nearly completely reversed sambutoxin-induced apoptosis. Accordingly, an in vivo study showed that sambutoxin exhibited potential antitumor activity in a BALB/c nude mouse xenograft model without significant systemic toxicity. Moreover, the expression changes in proteins related to the G2/M phase, DNA damage, and apoptosis in vivo were consistent with those in vitro. Importantly, sambutoxin has remarkable antiproliferative effects and is a promising anticarcinogen candidate for cancer treatment. |
Databáze: | OpenAIRE |
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