Antitumor Effect of Inula viscosa Extracts on DMBA-Induced Skin Carcinoma Are Mediated by Proteasome Inhibition.

Ouadie Mohamed El Yaagoubi,Ayoub Lahmadi,Said El Antri,Hassan Filali,Souad Aboudkhil,Abdelhakim Bouyahya,Hamid Samaki,Kosuru Ramoji

doi:10.1155/2021/6687589

Ouadie Mohamed El Yaagoubi, Ayoub Lahmadi + Show 6 more

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https://doi.org/10.1155/2021/6687589

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Abstract

The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of Inula viscosa extracts on skin carcinogenesis. Female Swiss albino mice were divided into five groups depending on the combination of skin cancer-inducing 7,12-dimethylbenz(a)anthracene (DMBA) and extract of Inula viscosa treatments. Histology of the affected skin and measurement of proteasome activity were performed to demonstrate the effect of Inula viscosa on mice. The identification of the molecules responsible for this inhibitory activity was carried out through the docking studies. The results showed that Inula viscosa extracts inhibit the development of papilloma in mice. Therefore, the best chemopreventive action of Inula viscosa was observed on mice in which extract treatment was performed before and after the induction of skin carcinogenesis. It was revealed that the ingestion of extracts Inula viscosa delays the formation of skin papillomas in animals and simultaneously decreases the size and number of papillomas, which is also reflected on the skin histology of the mice treated. Structure–activity relationship information obtained from component of Inula viscosa particularly tomentosin, inuviscolide, and isocosticacid demonstrated that distinct bonding modes in β1, β2, and β5 subunits determine its selectivity and potent inhibition for β5 subunit.

Highlights

The ubiquitin–proteasome system (UPS) plays a fundamental role in intracellular proteolysis
In order to evaluate the antitumor potential of Inula viscosa extract, three groups of mice were used, including a control group, a carcinogenesis group, and a group treated with Inula viscosa extract during the tumor initiation and promotion phases (Figure 1)
The mice treated with intraperitoneal injections of Inula viscosa extract demonstrated a reduced occurrence of the growth of papilloma compared to the carcinogen mice

Summary

Introduction

The ubiquitin–proteasome system (UPS) plays a fundamental role in intracellular proteolysis. Its central role is the degradation of abnormal proteins. It is vital for the regulated degradation of intracellular proteins and is directly involved in the regulation of most biological processes such as cell cycle, apoptosis, muscle differentiation, or immune response [1]. At the heart of this system is the proteasome, which is an essential protease in eukaryotes. The proteolytic core of this complex called proteasome 20S is shaped like a hollow cylinder containing the catalytic sites in internal cavity. Crystal structure (PDB: 4R3O) shows that the active sites of the 20S proteasome are mainly located on the β1, β2, and β5 subunits, which have caspase-like (C-L), trypsin-like (T-L), and chymotrypsin-like (ChT-L) activities, respectively

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