title: NO-dependent attenuation of TPA-induced immunoinflammatory skin changes in Balb/c mice by pindolol, heptaminol or ATRA, but not by verapamil.
abstract: Recently a mouse skin carcinogenesis study reported that a β-blocker carvedilol displayed antitumor-properties via antihyperplastic effects. However, the antihyperplastic mechanism is unclear as the β-blocker is characterized with multiple pleiotropic effects including stimulation of endothelial NO release and verapamil-like calcium channel blocking activity. To investigate the nature and the origin of the antihyperplastic effects, we tested topical pretreatment with pindolol, heptaminol, ATRA or verapamil against Balb/c mouse ear skin hyperplasia that was induced by TPA. We found that pindolol, heptaminol or ATRA, but not verapamil, inhibited the TPA-induced immunoinflammatory skin changes in an NO-dependent manner, which included epidermal hyperplasia, skin edema and fibrosis. Furthermore, we also observed NO-dependent alleviation of the TPA-induced NK cell depletion in the ear tissues by heptaminol pretreatment. Together our results suggest that stimulation of NO generation from constitutive synthases may be primarily responsible for the reported antihyperplastic and NK cell-preserving effects of the β-blockers, and that similar effects may be observed in other immunity normalizing compounds that also promote endothelial NO synthesis.
authors.affiliation: Synergy Point Co., Sungnam, South Korea.
authors.forename: Jinhyuk F
authors.initials: JF
authors.lastname: Chung
authors.affiliation: Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Yoon
authors.affiliation: NanoBio-Chemistry Laboratory, Department of Chemistry, Chung-Ang University, Seoul, South Korea.
authors.forename: Seon Ah
authors.initials: SA
authors.lastname: Cheon
authors.affiliation: Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea.|Center for Biofluid and Biomimic Research, Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Seo
authors.affiliation: Center for Biofluid and Biomimic Research, Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.affiliation: Clinical Immunology, Laboratory Science Unit, International Vaccine Institute, Seoul, South Korea.
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Yang
authors.affiliation: Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Bumju
authors.initials: B
authors.lastname: Kim
authors.affiliation: NanoBio-Chemistry Laboratory, Department of Chemistry, Chung-Ang University, Seoul, South Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Joo
authors.affiliation: NanoBio-Chemistry Laboratory, Department of Chemistry, Chung-Ang University, Seoul, South Korea.
authors.forename: Tae Jung
authors.initials: TJ
authors.lastname: Park
authors.affiliation: Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Ki Hean
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea.|Center for Biofluid and Biomimic Research, Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D005260:Female; D005355:Fibrosis; D006535:Heptaminol / Q000494:pharmacology*; D006965:Hyperplasia; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010869:Pindolol / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D009569:Nitric Oxide; D006535:Heptaminol; D014212:Tretinoin; D010869:Pindolol; D014700:Verapamil; D013755:Tetradecanoylphorbol Acetate; D019331:NG-Nitroarginine Methyl Ester
keywords: beta-blocker; heptaminol; nitric oxide; phorbol; tumor promotion