The cyclized oligopeptide targeting LRP5/6-DKK1 interaction reduces the growth of tumor burden in a multiple myeloma mouse model

Abstract

DKK1 has been extensively investigated in mouse models of multiple myeloma where the disease develops osteolytic bone lesions in the advanced state. Myeloma patients have elevated DKK1 levels in the bone marrow plasma and serum, which are associated with focal bone lesions, and the elevated level of DKK1 inhibits the differentiation of osteoblast precursors. Present pharmaceutical approaches to target bone metastases are limited to antiresorptive agents such as bisphosphonates and denosumab. In this study, the cyclized oligopeptide against DKK1-LRP5/6 interaction was developed, and the effects of the oligopeptide on tumor burden were tested. The cyclized oligopeptide based on the DKK1-LRP5/6 interaction was synthesized chemically, and the cyclized oligopeptide containing NXI motif bound to the E1 domain of LRP5/6 effectively on SPR analysis. The NMR structure between the cyclized oligopeptide and the first propeller domain of LRP5 were assessed. The cyclized oligopeptide abrogated the Wnt–β-catenin signaling inhibited by DKK1 but not by sclerostin dose dependently. MOPC315.BM.Luc cells were injected into the tail vein and 5 days after injection, the cyclized oligopeptide was delivered subcutaneously 6 days a week for 4 weeks. Bioluminescence images showed that the treatment of cyclized oligopeptide reduced tumor burden compared to the vehicle group. RT-PCR and ALP staining showed increased expressions of osteoblast markers according to the treatment concentrations. In conclusion, the cyclized oligopeptide developed here can be another option for the treatment of tumor burden in multiple myeloma.