title: Hinokitiol, a tropolone derivative, inhibits mouse melanoma (B16-F10) cell migration and in vivo tumor formation.
abstract: Invasion and metastasis are the major causes of treatment failure in patients with cancer. Hinokitiol, a natural bioactive compound found in Chamacyparis taiwanensis, has been used in hair tonics, cosmetics, and food as an antimicrobial agent. In this study, we investigated the effects and possible mechanisms of action of hinokitiol on migration by the metastatic melanoma cell line, B16-F10, in which matrix metalloproteinase-1 (MMP-1) is found to be highly- expressed. Treatment with hinokitiol revealed a concentration-dependent inhibition of migration of B16-F10 melanoma cells. Hinokitiol appeared to achieve this effect by reducing the expression of MMP-1 and by suppressing the phosphorylation of mitogen- activated protein kinase (MAPK) signaling molecules such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). On the other hand, hinokitiol treatment reversed IκB-α degradation and inhibited the phosphorylation of p65 nuclear factor kappa B (NF-κB) and cJun in B16-F10 cells. In addition, hinokitiol suppressed the translocation of p65 NF-κB from the cytosol to the nucleus, suggesting reduced NF-κB activation. Consistent with these in vitro findings, our in vivo study demonstrated that hinokitiol treatment significantly reduced the total number of mouse lung metastatic nodules and improved histological alterations in B16-F10 injected C57BL/6 mice. These findings suggest that treatment of B16-F10 cells with hinokitiol significantly inhibits metastasis, possibly by blocking MMP-1 activation, MAPK signaling pathways and inhibition of the transcription factors, NF-κB and c-Jun, involved in cancer cell migration. These results may accelerate the development of novel therapeutic agents for the treatment of malignant cancers.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan; Division of Urology, Department of Surgery, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan.
authors.forename: Chien-Hsun
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Division of Urology, Department of Surgery, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Cardiology, Cathay General Hospital, Taipei, Taiwan.
authors.forename: Chao-Chien
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Research and Development, Institute of Ophthalmology, Joseph Eye Hospital, Tiruchirappalli 620001, Tamil Nadu, India.
authors.forename: Philip Aloysius
authors.initials: PA
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology, Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. Electronic address: tjaya_2002@yahoo.co.in.
authors.forename: Thanasekaran
authors.initials: T
authors.lastname: Jayakumar
authors.affiliation: Department of Pharmacology, Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. Electronic address: sheujr@tmu.edu.tw.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D039821:Monoterpenes; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D014334:Tropolone; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; C009479:beta-thujaplicin
keywords: Anticancer; Hinokitiol; MAPKs; MMP-1; NF-κB; Tumor nodules