Kim Jean, Oh Ju Hun, Harlem Heather, Culler Michael D, Ku Cheol Ryong, Lee Eun Jig
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea.
Endocrinol Metab (Seoul). 2020 Mar;35(1):177-187. doi: 10.3803/EnM.2020.35.1.177.
Acromegaly is a rare disease primarily caused by growth hormone (GH)-secreting pituitary adenomas, and its treatment is costly. Moreover, some patients are unresponsive to treatment. Hence, there are increasing efforts to develop new drugs with improved effectiveness for this disease. BIM23B065 is a novel chimeric molecule that acts on both somatostatin and dopamine receptors. This study aimed to investigate the effects of BIM23B065 compared with those of a somatostatin receptor analog and a dopamine agonist.
The effects of BIM23B065 on the proliferation, GH and insulin-like growth factor-1 (IGF-1) levels, and extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element binding (CREB) phosphorylation of GH3 cells were investigated with MTS assay, enzyme-linked immunosorbent assay, and Western blotting, respectively. The dosage and treatment duration of BIM23B065 were tested in animal models of GH-secreting pituitary adenoma. The effect of BIM23B065 (3 mg/kg/day) on changes in IGF-1 levels before and after treatment was further investigated.
, BIM23B065 treatment decreased GH release in the culture media and downregulated ERK 1/2 and CREB phosphorylation to 22% and 26%, respectively. , IGF-1 expression decreased to 50 % after 4 weeks of treatment with BIM23B065 using an osmotic pump implant. Moreover, magnetic resonance imaging results showed that the tumor size decreased significantly following treatment with BIM23B065 for 4 weeks.
The novel chimeric molecule was effective in decreasing IGF-1 and GH levels and may serve as an effective therapeutic agent for acromegaly.
肢端肥大症是一种罕见疾病，主要由分泌生长激素（GH）的垂体腺瘤引起，其治疗费用高昂。此外，一些患者对治疗无反应。因此，人们越来越努力开发对该疾病有效性更高的新药。BIM23B065是一种新型嵌合分子，作用于生长抑素和多巴胺受体。本研究旨在调查BIM23B065与生长抑素受体类似物和多巴胺激动剂相比的效果。
分别采用MTS法、酶联免疫吸附测定法和蛋白质印迹法研究BIM23B065对GH3细胞增殖、GH和胰岛素样生长因子-1（IGF-1）水平以及细胞外信号调节激酶（ERK）1/2和环磷酸腺苷反应元件结合蛋白（CREB）磷酸化的影响。在分泌GH的垂体腺瘤动物模型中测试了BIM23B065的剂量和治疗持续时间。进一步研究了BIM23B065（3毫克/千克/天）对治疗前后IGF-1水平变化的影响。
BIM23B065处理降低了培养基中的GH释放，并将ERK 1/2和CREB磷酸化分别下调至22%和26%。使用渗透泵植入物用BIM23B065治疗4周后，IGF-1表达下降至50%。此外，磁共振成像结果显示，用BIM23B065治疗4周后肿瘤大小显著减小。
这种新型嵌合分子在降低IGF-1和GH水平方面有效，可能作为肢端肥大症的有效治疗药物。
