Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
J Bone Miner Res. 2013 May;28(5):1229-42. doi: 10.1002/jbmr.1847.
Insulin-like growth factor 1 (IGF-1) plays an important role in both bone metabolism and breast cancer. In this study, we investigated the effects of the novel IGF-1 receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) on osteolytic bone disease associated with breast cancer. Human MDA-MB-231 and mouse 4T1 breast cancer cells enhanced osteoclast formation in receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulated bone marrow cultures, and these effects were significantly inhibited by PQIP. Functional studies in osteoclasts showed that PQIP inhibited both IGF-1 and conditioned medium-induced osteoclast formation by preventing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) activation without interfering with RANKL or M-CSF signaling. Treatment of osteoblasts with PQIP significantly inhibited the increase in RANKL/osteoprotegerin (OPG) ratio by IGF-1 and conditioned medium and totally prevented conditioned medium-induced osteoclast formation in osteoblast-bone marrow (BM) cell cocultures, thereby suggesting an inhibitory effect on osteoblast-osteoclast coupling. PQIP also inhibited IGF-1-induced osteoblast differentiation, spreading, migration, and bone nodule formation. Treatment with PQIP significantly reduced MDA-MB-231 conditioned medium-induced osteolytic bone loss in a mouse calvarial organ culture system ex vivo and in adult mice in vivo. Moreover, once daily oral administration of PQIP significantly decreased trabecular bone loss and reduced the size of osteolytic bone lesions following 4T1 intratibial injection in mice. Quantitative histomorphometry showed a significant reduction in bone resorption and formation indices, indicative of a reduced rate of cancer-associated bone turnover. We conclude that inhibition of IGF-1 receptor tyrosine kinase activity by PQIP suppresses breast cancer-induced bone turnover and osteolysis. Therefore, PQIP, and its novel derivatives that are currently in advanced clinical development for the treatment of a number of solid tumors, may be of value in the treatment of osteolytic bone disease associated with breast cancer.
胰岛素样生长因子 1（IGF-1）在骨代谢和乳腺癌中都发挥着重要作用。在这项研究中，我们研究了新型 IGF-1 受体酪氨酸激酶抑制剂 cis-3-[3-(4-甲基-哌嗪-1-基)-环丁基]-1-(2-苯基-喹啉-7-基)-咪唑[1,5-a]吡嗪-8-基胺（PQIP）对乳腺癌相关溶骨性骨病的影响。人 MDA-MB-231 和小鼠 4T1 乳腺癌细胞在核因子-κB 配体（RANKL）和巨噬细胞集落刺激因子（M-CSF）刺激的骨髓培养物中增强破骨细胞形成，而 PQIP 显著抑制了这些作用。破骨细胞的功能研究表明，PQIP 通过阻止磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）的激活来抑制 IGF-1 和条件培养基诱导的破骨细胞形成，而不干扰 RANKL 或 M-CSF 信号。PQIP 处理成骨细胞可显著抑制 IGF-1 和条件培养基引起的 RANKL/骨保护素（OPG）比值升高，并完全防止条件培养基诱导的成骨细胞-骨髓（BM）细胞共培养中的破骨细胞形成，从而提示对成骨细胞-破骨细胞偶联的抑制作用。PQIP 还抑制 IGF-1 诱导的成骨细胞分化、铺展、迁移和骨结节形成。PQIP 处理可显著减少 MDA-MB-231 条件培养基诱导的小鼠颅盖器官培养系统和体内成骨细胞骨丢失。此外，PQIP 每天一次口服给药可显著减少 4T1 胫骨内注射后小鼠小梁骨丢失，并减小溶骨性骨病变的大小。定量组织形态计量学显示，骨吸收和形成指数显著降低，提示癌症相关骨转换率降低。我们得出结论，PQIP 抑制 IGF-1 受体酪氨酸激酶活性可抑制乳腺癌引起的骨转换和溶骨。因此，PQIP 及其目前正在多个实体瘤的临床开发后期的新型衍生物可能对治疗与乳腺癌相关的溶骨性骨病有价值。
