PI3K 抑制剂 BKM120 对多发性骨髓瘤肿瘤生长和溶骨性骨病的影响。
The effect of the PI3K inhibitor BKM120 on tumour growth and osteolytic bone disease in multiple myeloma.
机构信息
Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Australia; Centre for Cancer Biology and Hanson Centre for Cancer Research, SA Pathology, Australia; Centre for Stem Cell Research and Centre for Personalised Cancer Medicine, University of Adelaide, Australia; The South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Australia; Centre for Stem Cell Research and Centre for Personalised Cancer Medicine, University of Adelaide, Australia; The South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Australia.
出版信息
Leuk Res. 2015 Mar;39(3):380-7. doi: 10.1016/j.leukres.2014.12.015. Epub 2015 Jan 7.
The plasma cell malignancy multiple myeloma (MM) is unique amongst haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt pathway mediates proliferation, survival and drug resistance in MM plasma cells and is also involved in regulating the formation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts. NVP-BKM120 (Buparlisib, Novartis) is a PI3K inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we have examined the anti-tumorigenic effects of BKM120 in an immunocompetent mouse model of MM and its effects on osteoblast and osteoclast formation and function. BKM120 treatment (40 mg/kg) resulted in a significant decrease in serum paraprotein and tumour burden, and μCT analysis of the proximal tibia revealed a significant reduction in the number of osteolytic bone lesions in BKM120-treated animals. BKM120 also mediated a significant increase in serum levels of the osteoblast marker P1NP, and a significant decrease in serum levels of the osteoclast marker TRAcP5. In vitro, BKM120 decreased MM plasma cell proliferation, osteoclast formation and function, and promoted osteoblast formation and function. These findings suggest that, in addition to its anti-tumour properties, BKM120 could be used to treat osteolytic bone disease in MM patients.
浆细胞恶性肿瘤多发性骨髓瘤（MM）在其引起破骨细胞介导的骨骼破坏的能力方面在血液恶性肿瘤中是独特的。PI3K/Akt 通路介导 MM 浆细胞的增殖、存活和耐药性，并且还参与调节成骨细胞和破骨细胞的形成和活性。NVP-BKM120（Buparlisib，诺华公司）是一种正在几种肿瘤环境中进行临床评估的 PI3K 抑制剂。在这项研究中，我们研究了 BKM120 在免疫活性 MM 小鼠模型中的抗肿瘤作用及其对成骨细胞和破骨细胞形成和功能的影响。BKM120 治疗（40mg/kg）导致血清副蛋白和肿瘤负担显著下降，并且对近端胫骨的 μCT 分析显示 BKM120 治疗动物的溶骨性骨病变数量显著减少。BKM120 还介导了成骨细胞标志物 P1NP 的血清水平显著增加，以及破骨细胞标志物 TRAcP5 的血清水平显著降低。体外，BKM120 降低了 MM 浆细胞的增殖、破骨细胞的形成和功能，并促进了成骨细胞的形成和功能。这些发现表明，除了其抗肿瘤特性外，BKM120 还可用于治疗 MM 患者的溶骨性骨疾病。
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