Seo Ean-Jeong, Sugimoto Yoshikazu, Greten Henry Johannes, Efferth Thomas
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Front Pharmacol. 2018 Oct 8;9:1030. doi: 10.3389/fphar.2018.01030. eCollection 2018.
Bromocriptine is an ergot alkaloid and dopamine D 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, 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.
溴隐亭是一种麦角生物碱和多巴胺D受体激动剂，用于治疗帕金森病、肢端肥大症、高泌乳素血症和溢乳症，最近也用于治疗糖尿病。该药物对垂体激素依赖性肿瘤（泌乳素瘤和生长激素分泌性腺瘤）也有活性。我们研究了溴隐亭是否也能抑制激素非依赖性和多药耐药（MDR）肿瘤。我们发现溴隐亭对药物敏感的CCRF-CEM细胞、多药耐药的CEM/ADR5000白血病细胞以及野生型或多药耐药的ABCB5转染的HEK293细胞系具有细胞毒性，但对敏感的或BCRP转染的多药耐药MDA-MB-231乳腺癌细胞没有细胞毒性。分子对接显示溴隐亭与NF-κB通路蛋白强烈结合，并且与结合DNA的NF-κB的相互作用比游离的NF-κB更强，这表明溴隐亭可能抑制NF-κB与DNA的结合。此外，通过SEAP驱动的NF-κB报告基因细胞试验，溴隐亭降低了NF-κB活性。在一组60种NCI细胞系中，赋予多药耐药性的ABC转运蛋白（ABCB1、ABCB5、ABCC1和ABCG2）以及其他耐药介导因子（EGFR、突变的TP53和IκB）的表达与细胞对溴隐亭的反应无关。细胞对溴隐亭的反应与通常参与多药耐药的抗癌药物（如蒽环类药物、生物碱、紫杉烷、鬼臼毒素等）之间没有相关性。对这些细胞系基于微阵列的mRNA表达进行COMPARE分析发现，来自各种功能组的基因，如核糖体蛋白、转录、翻译、DNA修复、DNA损伤、蛋白质折叠、线粒体呼吸链和趋化因子，与细胞对溴隐亭的反应相关。我们的结果表明，溴隐亭以激素非依赖性方式抑制具有不同耐药机制的耐药肿瘤细胞。由于难治性和其他耐药肿瘤是成功进行癌症化疗的主要挑战，溴隐亭可考虑重新用于癌症治疗。
