Structural simulation of adenosine phosphate via plumbagin and zoledronic acid competitively targets JNK/Erk to synergistically attenuate osteoclastogenesis in a breast cancer model

• DOI: 10.1038/cddis.2016.11
• Publication Date: 2016-02-12T01:23:33Z
• Authors: H Qiao; T-y Wang; Z-f Yu; X-g Han; X-q Liu; Y-g Wang; Q-m Fan; A Qin; T-t Tang
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Diphosphonates; Adenine Nucleotides; MAP Kinase Signaling System; Imidazoles; JNK Mitogen-Activated Protein Kinases; Mice, Nude; Osteoclasts; Breast Neoplasms; Drug Synergism; Osteolysis; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Original Article; Female; Phosphorylation; Naphthoquinones

Abstract The treatment of breast cancer-induced osteolysis remains a challenge in clinical settings. Here, we explored the effect and mechanism combined with zoledronic acid (ZA) plumbagin (PL), widely investigated component derived from Plumbago zeylanica , against osteoclastogenesis. We found that PL ZA suppressed cell viability precursor osteoclasts synergistically inhibited MDA-MB-231-induced osteoclast formation (combination index=0.28) abrogation recombinant mouse receptor activator nuclear factor- κ B ligand (RANKL)-induced activation NF- B/MAPK (nuclear B/mitogen-activated protein kinase) pathways. Molecular docking suggested putative binding area within c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk) protease active sites through structural mimicking adenosine phosphate (ANP) by spatial combination ZA. A homogeneous time-resolved fluorescence assay further illustrated direct competitiveness dual drugs ANP to phosphorylated JNK/Erk, contributing downstream expression c-Jun/c-Fos/NFATc-1 factor activated T cells, cytoplasmic, calcineurin-dependent 1). Then, vivo testing demonstrated administration attenuated cancer growth bone microenvironment. Additionally, these molecules prevented destruction proximal tibia, significant reduction tartrate-resistant phosphatase (TRAcP)-positive cells potentiation apoptotic greater extent when than were applied independently. Altogether, could significantly suppress osteoclastogenesis inhibit tumorigenesis both vitro simulating structure competitively phosphorylation (JNK/Erk).