RESUMEN
The plasma cell malignancy multiple myeloma (MM) is unique among haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt/mTOR 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-BEZ235 is a dual pan class I PI3K and mTOR inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we examined the anti-tumorigenic effects of BEZ235 in an immunocompetent mouse model of MM and assessed the effects of BEZ235 on osteoblast and osteoclast formation and function. BEZ235 treatment (50 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 BEZ235-treated animals. Levels of the serum osteoblast marker P1NP were significantly higher in BEZ235-treated animals, while levels of the osteoclast marker TRAcP5 were reduced. In vitro, BEZ235 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, BEZ235 could be useful in treating osteolytic bone disease in MM patients.
Asunto(s)
Enfermedades Óseas/tratamiento farmacológico , Enfermedades Óseas/etiología , Imidazoles/farmacología , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Osteólisis/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Animales , Enfermedades Óseas/patología , Línea Celular , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Imidazoles/administración & dosificación , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Mieloma Múltiple/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Carga Tumoral/efectos de los fármacosRESUMEN
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.