Repurposing of Bromocriptine for Cancer Therapy.

Ean-Jeong Seo,Yoshikazu Sugimoto,Thomas Efferth,Henry Johannes Greten

doi:10.3389/fphar.2018.01030

Abstract

Bromocriptine is an ergot alkaloid and dopamine D2 receptor agonist used to treat Parkinson’s disease, acromegaly, hyperprolactinemia, and galactorrhea, and more recently diabetes mellitus. The drug is also active against pituitary hormone-dependent tumors (prolactinomas and growth-hormone producing adenomas). We investigated, whether bromocriptine also inhibits hormone-independent and multidrug-resistant (MDR) tumors. We found that bromocriptine was cytotoxic towards drug-sensitive CCRF-CEM, multidrug-resistant CEM/ADR5000 leukemic cells as well as wild-type or multidrug-resistant ABCB5-transfected HEK293 cell lines, but not sensitive or BCRP-transfected multidrug-resistant MDA-MB-231 breast cancer cells. Bromocriptine strongly bound to NF-κB pathway proteins as shown by molecular docking and interacted more strongly with DNA-bound NF-κB than free NF-κB, indicating that bromocriptine may inhibit NF-κB binding to DNA. Furthermore, bromocriptine decreased NF-κB activity by a SEAP-driven NF-κB reporter cell assay. The expression of MDR-conferring ABC-transporters (ABCB1, ABCB5, ABCC1, and ABCG2) and other resistance-mediating factors (EGFR, mutated TP53, and IκB) did not correlate with cellular response to bromocriptine in a panel of 60 NCI cell lines. There was no correlation between cellular response to bromocriptine and anticancer drugs usually involved in MDR (e.g., anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and others). COMPARE analysis of microarray-based mRNA expression in these cell lines revealed that genes from various functional groups such as ribosomal proteins, transcription, translation, DNA repair, DNA damage, protein folding, mitochondrial respiratory chain, and chemokines correlated with cellular response to bromocriptine. Our results indicate that bromocriptine inhibited drug-resistant tumor cells with different resistance mechanisms in a hormone-independent manner. As refractory and otherwise drug-resistant tumors represent a major challenge to successful cancer chemotherapy, bromocriptine may be considered for repurposing in cancer therapy.

Highlights

Bromocriptine is an ergot alkaloid and dopamine D2 receptor agonist that has been used to treat Parkinson’s disease by affecting dopamine receptor signaling in the nigrostriatal tract and to treat hyperprolactinemia and acromegaly through tuberoinfundibular pathways (Kvernmo et al, 2006)
We addressed the question whether bromocriptine is active against hormone-dependent tumors and might exert cytotoxic activity against cancer cells in a hormone-independent fashion
Protein and mRNA expression as well as DNA mutations of ATP-binding cassette (ABC)-transporters (ABCB1, ABCB5, ABCC1, and ABCG2) and other mechanisms of drug resistance (EGFR, mutated TP53, NFκB, and IκB) in the National Cancer Institute (NCI) cell line panel was correlated with the log10IC50 values for bromocriptine

Summary

INTRODUCTION

Bromocriptine is an ergot alkaloid and dopamine D2 receptor agonist that has been used to treat Parkinson’s disease by affecting dopamine receptor signaling in the nigrostriatal tract and to treat hyperprolactinemia and acromegaly through tuberoinfundibular pathways (Kvernmo et al, 2006). It showed inhibitory effects on serotonin turnover in the central nervous system (CNS; Goldstein, 1980). Bromocriptine inhibited prolactin-secretion resulting in suppression of lactation and bound to dopamine D2 receptor (Radad et al, 2005) Prolactin exerts both behavioral effects in the brain (Torner et al, 2001; Brunton and Russell, 2010). We investigated the inhibitory effect of bromocriptine toward NF-κB using in silico molecular docking and NF-κB reporter cell assay, since several studies showed that bromocriptine affects NF-κB

MATERIALS AND METHODS

RESULTS

DISCUSSION