title: A novel herbal medicine, KIOM-C, induces autophagic and apoptotic cell death mediated by activation of JNK and reactive oxygen species in HT1080 human fibrosarcoma cells.
abstract: KIOM-C was recently demonstrated to have anti-metastatic activity in highly malignant cancer cells via suppression of NF-κB-mediated MMP-9 activity. In addition, it was reported to be effective for clearance of the influenza virus by increasing production of anti-viral cytokines, such as TNF-α and IFN-γ, and efficacious in the treatment of pigs suffering from porcine circovirus-associated disease (PCVAD). In this study, we investigated whether KIOM-C induces cancer cell death and elucidated the underlying anti-cancer mechanisms. In addition, we examined whether KIOM-C oral administration suppresses in vivo tumor growth of HT1080 cells in athymic nude mice. We initially found that KIOM-C at concentrations of 500 and 1000 µg/ml caused dose- and time-dependent cell death in cancer cells, but not normal hepatocytes, to approximately 50% of control levels. At the early stage of KIOM-C treatment (12 h), cells were arrested in G1 phase, which was accompanied by up-regulation of p21 and p27, down-regulation of cyclin D1, and subsequent increases in apoptotic and autophagic cells. Following KIOM-C treatment, the extent of caspase-3 activation, PARP cleavage, Beclin-1 expression, and LC3-II conversion was remarkably up-regulated, but p62 expression was down-regulated. Phosphorylation of AMPK, ULK, JNK, c-jun, and p53 was increased significantly in response to KIOM-C treatment. The levels of intracellular ROS and CHOP expression were also increased. In particular, the JNK-specific inhibitor SP600125 blocked KIOM-C-induced ROS generation and CHOP expression almost completely, which consequently almost completely rescued cell death, indicating that JNK activation plays a critical role in KIOM-C-induced cell death. Furthermore, daily oral administration of 85 and 170 mg/kg KIOM-C efficiently suppressed the tumorigenic growth of HT1080 cells, without systemic toxicity. These results collectively suggest that KIOM-C efficiently induces cancer cell death by both autophagy and apoptosis via activation of JNK signaling pathways, and KIOM-C represents a safe and potent herbal therapy for treating malignancies.
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Daejeon, Republic of Korea.
authors.forename: Aeyung
authors.initials: A
authors.lastname: Kim
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Daejeon, Republic of Korea.
authors.forename: Minju
authors.initials: M
authors.lastname: Im
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Daejeon, Republic of Korea.
authors.forename: Nam-Hui
authors.initials: NH
authors.lastname: Yim
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Daejeon, Republic of Korea.
authors.forename: Taesoo
authors.initials: T
authors.lastname: Kim
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Daejeon, Republic of Korea.
authors.forename: Jin Yeul
authors.initials: JY
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D029001:Herbal Medicine / Q000379:methods; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010946:Plants, Medicinal; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases