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

doi:10.18632/oncotarget.10217

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.

Highlights

Chronic neuropsychological stress causing the activation of β-adrenergic receptors leads to increased rate of metastasis and tumor recurrence by inhibiting normal immune functions in cancer patients [1, 2]
Together our results suggest that stimulation of nitric oxide (NO) generation from constitutive synthases may be primarily responsible for the reported antihyperplastic and natural killer cell (NK cell)-preserving effects of the β-blockers, and that similar effects may be observed in other immunity normalizing compounds that promote endothelial NO synthesis
TPAinduced activation of fibroblasts is critical during the tumor promotion process as they maintain the chronic inflammation state by attracting macrophages and neutrophils through high-level secretion of monocyte chemotactic protein-1 (MCP1) [14, 15]

Summary

Introduction

Chronic neuropsychological stress causing the activation of β-adrenergic receptors leads to increased rate of metastasis and tumor recurrence by inhibiting normal immune functions in cancer patients [1, 2]. Based on this idea, Powe et al reported that long-term use of general β-adrenergic receptor inhibitors (β-blockers) was associated with reduced incidence of metastasis and secondary tumor formation among breast cancer patients [2], while later studies reported that only certain subsets of β-blockers were clinically effective in cancer treatments. These observations collectively suggest that the clinical benefits of using β-blockers in cancer treatments may not be generalized to other β-blockers, and understanding the responsible mechanism is critical in identification of the optimal β-blockers for adjuvant cancer therapeutic use

Methods

Results

Conclusion