Antitheilerial Activity of the Anticancer Histone Deacetylase Inhibitors.

Madhumanti Barman,Debabrata Dandasena,Sonti Roy,Paresh Sharma,Sonam Kamble,Akash Suresh,Siva Singothu,Vasundhra Bhandari

doi:10.3389/fmicb.2021.759817

Abstract

The apicomplexan parasite, Theileria annulata, is the most prevalent hemoprotozoan in livestock, causing significant economic losses worldwide. It is essential to develop new and improved therapeutics, as current control measures are compromised by the development of resistance against the only available antitheilerial drug, buparvaquone (BPQ). Histone deacetylase inhibitors (HDACi) were shown to treat cancer effectively and revealed in vitro antiparasitic activity against apicomplexan parasites such as Plasmodium and Toxoplasma. In this study, we investigated the antitheilerial activity of the four anti-cancer HDACi (vorinostat, romidepsin, belinostat, and panobinostat) against the schizont stage of T. annulata parasites. All four HDACi showed potent activity and increased hyperacetylation of the histone-4 protein. However, based on the low host cell cytotoxicity and IC50 values, vorinostat (0.103 μM) and belinostat (0.069 μM) were the most effective showing antiparasitic activity. The parasite-specific activities of the HDACi (vorinostat and belinostat) were evaluated by western blotting using parasite-specific antibodies and in silico analysis. Both vorinostat and belinostat reduced the Theileria infected cell viability by downregulating anti-apoptotic proteins and mitochondrial dysfunction, leading to caspase-dependent cell apoptosis. The HDACi caused irreversible and antiproliferative effects on the Theileria infected cell lines. Our results collectively showed that vorinostat and belinostat could be used as an alternative therapy for treating Theileria parasites.

Highlights

Bovine Theileriosis (BT), caused by Theileria parasites, is an economically significant parasitic disease (Brown, 1990)
For assessing the antitheilerial activity of the Histone deacetylase inhibitors (HDACi), invitro cultured T. annulata parasites were challenged with different concentrations of the compounds
A comparison was made for the effectiveness of the HDACi based on the IC50 values between the Theileria and Plasmodium parasites

Summary

INTRODUCTION

Bovine Theileriosis (BT), caused by Theileria parasites, is an economically significant parasitic disease (Brown, 1990). The current schizont stage attenuated vaccine (Rakshavac-T) used in India has associated drawbacks like the infrastructure of vaccine production, its distribution, and cold chain maintenance; it is not commonly used in the field (Jeyabal et al, 2012). This leads to almost complete dependency on chemotherapy for BT treatment. We tested antitheilerial activity of the four HDACi: vorinostat, romidepsin, belinostat, and panobinostat against the T. annulata parasites. We have done molecular docking studies for showing the binding of HDACi to the Theileria specific proteins using in silico studies

MATERIALS AND METHODS

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT