NO-dependent attenuation of TPA-induced immunoinflammatory skin changes in Balb/c mice by pindolol, heptaminol or ATRA, but not by verapamil

• Published in: Oncotarget Vol. 7; no. 30; pp. 47576 - 47585
• Main Authors: Chung, Jinhyuk F, Yoon, Calvin J, Cheon, Seon Ah, Seo, Eun Seok, Park, Sung Ho, Yang, Jae Seung, Kim, Bumju, Joo, Min Young, Park, Tae Jung, Kim, Ki Hean, Sood, Anil K, Lee, Sang Joon
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 26.07.2016
• Subjects: Animals; Female; Fibrosis; Heptaminol - pharmacology; Hyperplasia; Killer Cells, Natural - immunology; Mice; Mice, Inbred BALB C; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - physiology; Pindolol - pharmacology; Research Paper; Skin - drug effects; Skin - pathology; Tetradecanoylphorbol Acetate - pharmacology; Tretinoin - pharmacology; Verapamil - pharmacology; nitric oxide; beta-blocker; heptaminol; tumor promotion; phorbol
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10217

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.