title: Hinokitiol Exerts Anticancer Activity through Downregulation of MMPs 9/2 and Enhancement of Catalase and SOD Enzymes: In Vivo Augmentation of Lung Histoarchitecture.
abstract: Melanoma is extremely resistant to chemotherapy and the death rate is increasing hastily worldwide. Extracellular matrix promotes the migration and invasion of tumor cells through the production of matrix metalloproteinase (MMP)-2 and -9. Evidence has shown that natural dietary antioxidants are capable of inhibiting cancer cell growth. Our recent studies showed that hinokitiol, a natural bioactive compound, inhibited vascular smooth muscle cell proliferation and platelets aggregation. The present study is to investigate the anticancer efficacy of hinokitiol against B16-F10 melanoma cells via modulating tumor invasion factors MMPs, antioxidant enzymes in vitro. An in vivo mice model of histological investigation was performed to study the patterns of elastic and collagen fibers. Hinokitiol inhibited the expression and activity of MMPs-2 and -9 in B16-F10 melanoma cells, as measured by western blotting and gelatin zymography, respectively. An observed increase in protein expression of MMPs 2/9 in melanoma cells was significantly inhibited by hinokitiol. Notably, hinokitiol (1-5 μM) increased the activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) from the reduction in melanoma cells. Also, hinokitiol (2-10 µM) concentration dependently reduced in vitro Fenton reaction induced hydroxyl radical (OH·) formation. An in vivo study showed that hinokitiol treatment increased elastic fibers (EF), collagens dispersion, and improved alveolar alterations in the lungs of B16/F10 injected mice. Overall, our findings propose that hinokitiol may be a potent anticancer candidate through down regulation of MMPs 9/2, reduction of OH· production and enhancement of antioxidant enzymes SOD and CAT.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan. DAR87@tpech.gov.tw.|Division of Urology, Department of Surgery, Taipei City Hospital, Zhongxiao Branch, Taipei 115, Taiwan. DAR87@tpech.gov.tw.
authors.forename: Chien-Hsun
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. tjaya_2002@yahoo.co.in.
authors.forename: Thanasekaran
authors.initials: T
authors.lastname: Jayakumar
authors.affiliation: Department of Cardiology, Cathay General Hospital, Taipei 106, Taiwan. change@seed.net.tw.
authors.forename: Chao-Chien
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Anatomy, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan. thfong@tmu.edu.tw.
authors.forename: Tsorng-Harn
authors.initials: TH
authors.lastname: Fong
authors.affiliation: Division of Urology, Department of Surgery, Taipei City Hospital, Zhongxiao Branch, Taipei 115, Taiwan. shlu77777@gmail.com.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Lu
authors.affiliation: Department of Microbiology, Institute of Ophthalmology, Joseph Eye Hospital, Tiruchirappalli 620001, Tamil Nadu, India. thomasdiagnosticcentre@gmail.com.
authors.forename: Philip Aloysius
authors.initials: PA
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. prof.choy@gmail.com.|Department of Emergency, Min-Sheng General Hospital, Taoyuan 330, Taiwan. prof.choy@gmail.com.
authors.forename: Cheuk-Sing
authors.initials: CS
authors.lastname: Choy
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan. sheujr@tmu.edu.tw.|Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. sheujr@tmu.edu.tw.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D039821:Monoterpenes; D017665:Hydroxyl Radical; D014334:Tropolone; D002374:Catalase; D013482:Superoxide Dismutase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C009479:beta-thujaplicin
keywords: MMPs; antioxidant enzymes; elastic fiber; hinokitiol; histology; melanoma