Research Papers:

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

Jinhyuk F. Chung _, Calvin J. Yoon, Seon Ah Cheon, Eun Seok Seo, Sung Ho Park, Jae Seung Yang, Bumju Kim, Min Young Joo, Tae Jung Park, Ki Hean Kim, Anil K. Sood and Sang Joon Lee

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Oncotarget. 2016; 7:47576-47585. https://doi.org/10.18632/oncotarget.10217

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Jinhyuk F. Chung1,*, Calvin J. Yoon2,*, Seon Ah Cheon4,*, Eun Seok Seo2,3, Sung Ho Park3, Jae Seung Yang5, Bumju Kim2, Min Young Joo4, Tae Jung Park4, Ki Hean Kim2, Anil K. Sood6, Sang Joon Lee2,3

1Synergy Point Co., Sungnam, South Korea

2Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea

3Center for Biofluid and Biomimic Research, Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea

4NanoBio-Chemistry Laboratory, Department of Chemistry, Chung-Ang University, Seoul, South Korea

5Clinical Immunology, Laboratory Science Unit, International Vaccine Institute, Seoul, South Korea

6Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

*Co-first authors

Correspondence to:

Jinhyuk F. Chung, email: [email protected]

Tae Jung Park, email: [email protected]

Kihean Kim, email: [email protected]

Sang Joon Lee, email: [email protected]

Keywords: nitric oxide, beta-blocker, heptaminol, tumor promotion, phorbol

Received: May 03, 2016     Accepted: May 29, 2016     Published: June 22, 2016


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.

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