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.