Wang Yongqiang, Mei Yixue, Song Yushan, Bachus Carly, Sun Chunxiang, Sheshbaradaran Hooshmand, Glogauer Michael
Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
Eur J Pharmacol. 2020 Dec 15;889:173613. doi: 10.1016/j.ejphar.2020.173613. Epub 2020 Sep 29.
AP-002 is a novel, gallium-based, anti-cancer oral compound in clinical development for cancer patients with bone metastases. We examined the effects of AP-002 on osteoclastogenesis, fusion, and osteogenesis. AP-002 exhibited a dramatic effect on osteoclast function without causing osteoclast cell death. The expression of tartrate-resistant acid phosphatase and cathepsin K mRNA levels was down-regulated in RAW264.7 cells treated with AP-002 in the presence of soluble receptor activator of NF-κB ligand. AP-002 was also found to block the fusion of osteoclasts from RAW264.7 cells. AP-002 had a similar inhibitory effect on RANKL-induced mouse primary bone marrow monocytes fusion. Human blood monocytes treated with AP-002 failed to form TRAcP/ACP5-positive cells. AP-002 caused these inhibitory effects without causing osteoclast cell death, which was in contrast to zoledronic acid controls. Furthermore, unlike zoledronic acid, AP-002 did not inhibit Rac1 activation. Gene expression analysis by microarrays showed that AP-002 significantly reverses the effects of RANKL-induced gene expression. These include several key osteoclast-differentiation/function-associated genes such as: Scinderin, OCSTAMP, Atp6v0d2, OSCAR, RhoU, Usp18, MMP9, and Trim30. The difference between AP-002 and zoledronic acid is also seen in its effects on osteogenesis. Osteoblast mineralization was promoted by AP-002 (0.1-3.0 μM), whereas zoledronic acid showed toxicity to osteoblasts at the concentration >0.5 μM, in the same dose range where it causes osteoclast cell death. Zoledronic acid therefore has no therapeutic window in its toxic effect on osteoclasts and osteoblasts. AP-002 promotes osteogenesis in this therapeutic window, while blocking osteoclast development. We therefore conclude that AP-002 has potential as a new anti-bone resorption agent, with a mechanism of action different compared with other currently marketed anti-bone resorption agents.
AP - 002是一种新型的基于镓的抗癌口服化合物，正处于针对骨转移癌患者的临床开发阶段。我们研究了AP - 002对破骨细胞生成、融合及成骨作用的影响。AP - 002对破骨细胞功能具有显著作用，但不会导致破骨细胞死亡。在用AP - 002处理的RAW264.7细胞中，在存在NF - κB配体可溶性受体激活剂的情况下，抗酒石酸酸性磷酸酶和组织蛋白酶K的mRNA水平表达下调。还发现AP - 002可阻断RAW264.7细胞来源的破骨细胞融合。AP - 002对RANKL诱导的小鼠原代骨髓单核细胞融合具有类似的抑制作用。用AP - 002处理的人血单核细胞无法形成抗酒石酸酸性磷酸酶/ACP5阳性细胞。AP - 002产生这些抑制作用时不会导致破骨细胞死亡，这与唑来膦酸对照不同。此外，与唑来膦酸不同，AP - 002不会抑制Rac1激活。通过微阵列进行的基因表达分析表明，AP - 002可显著逆转RANKL诱导的基因表达效应。这些基因包括几个与破骨细胞分化/功能相关的关键基因，如：肌切蛋白、破骨细胞刺激跨膜蛋白、ATP酶H +转运V0亚基d2、破骨细胞相关受体、RhoU、泛素特异性蛋白酶18、基质金属蛋白酶9和TRIM30。AP - 002与唑来膦酸的差异还体现在其对成骨作用的影响上。AP - 002（0.1 - 3.0 μM）可促进成骨细胞矿化，而唑来膦酸在浓度>0.5 μM时对成骨细胞表现出毒性，该浓度范围与它导致破骨细胞死亡的浓度相同。因此，唑来膦酸对破骨细胞和成骨细胞的毒性作用没有治疗窗。AP - 002在这个治疗窗内促进成骨，同时阻断破骨细胞发育。因此，我们得出结论，AP - 002有潜力成为一种新型抗骨吸收药物，其作用机制与目前市场上其他抗骨吸收药物不同。
