Tebrophen — An Old Polyphenol Drug with Anticancer Potential †

Ivica Rubelj,Višnja Stepanić,Donatella Verbanac,Krunoslav Nujić,Dubravko Jelić,Milena Ivanković,Andrea Ćukušić Kalajžić,Nikolina Škrobot Vidaček,Mario Matijašić

doi:10.3390/molecules17077864

Abstract

In vitro high-throughput screening was carried out in order to detect new activities for old drugs and to select compounds for the drug development process comprising new indications. Tebrophen, a known antiviral drug, was found to inhibit activities on inflammation and cancer related targets. In primary screening this semisynthetic halogenated polyphenol was identified to inhibit the activities of kinases ZAP-70 and Lck (IC50 0.34 µM and 16 µM, respectively), as well as hydrolase DPPIV (at 80 µM 41% inhibition). Next, it showed no cytotoxic effects on standard cell lines within 24 h. However, tebrophen slowed propagation of breast cancer (MDA-MB-231), osteosarcoma (U2OS) and cervical carcinoma (HeLa), through at least 35 population doublings in a dose-dependent manner. It completely stopped the division of the prostate cancer (PC3) cell line at 50 µM concentration and the cells entered massive cell death in less than 20 days. On the other hand, tebrophen did not influence the growth of normal fibroblasts. According to the measured oxidative burst and estimated in silico parameters its direct antioxidative ability is limited. The obtained results indicate that tebrophen can be considered a promising lead molecule for generating more soluble derivatives with specific anticancer efficacy.

Highlights

In order to acquire new drug applications, systematic screening of a unique compound library [1], was carried out on different biological targets [2]
Tebrophen (3,3',5,5'-tetrabromobiphenyl2,2',4,4'-tetrol, Figure 1), a drug known for the treatment of viral eye diseases, was found to inhibit activities of inflammation and cancer related targets, such as tyrosine kinases Lck and ZAP-70, and hydrolase Dipeptidyl peptidase IV (DPPIV/CD26), recently extensively studied [5]
In order to assess cell specificity, we investigated the influence of tebrophen on the growth dynamics [population doublings (PDs)] of normal human fibroblasts and of a few specific cancer cell lines in which inhibition of such targets may reduce or even stop their propagation

Summary

Introduction

In order to acquire new drug applications, systematic screening of a unique compound library [1], was carried out on different biological targets [2]. This high-throughput screening (HTS) started in silico and proceeded in vitro [3,4]. By applying this approach, tebrophen (3,3',5,5'-tetrabromobiphenyl2,2',4,4'-tetrol, Figure 1), a drug known for the treatment of viral eye diseases, was found to inhibit activities of inflammation and cancer related targets, such as tyrosine kinases Lck and ZAP-70, and hydrolase Dipeptidyl peptidase IV (DPPIV/CD26), recently extensively studied [5]. Our experience in HTS assessment of the inhibitory effects of polyphenolic compounds on kinases [13,14], was valuable for the verification and follow-up of the tebrophen afterward screening

Results

Discussion

Conclusion