piperidines and Osteolysis

Primitive lymphomas of the bone are exceptional tumors, representing 4% of all non-Hodgkin lymphomas. The location at the skull remains the rarest. We report the case of a 56 year old patient with lytic lesions in the skull of a small cell lymphoma B, treated with primary chemotherapy and intensity-modulated radiotherapy in arctherapy with a dose of 30Gy in 15 fractions. With a follow-up time of 18 months after the end of treatment, the patient has no sign of disease evolution.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Craniotomy; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasms, Second Primary; Osteolysis; Parietal Bone; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Radiotherapy, Intensity-Modulated; Remission Induction; Skull Neoplasms

Cancer-associated bone disease is a serious complication in bone sarcomas and metastatic carcinomas of breast and prostate origin. Monoacylglycerol lipase (MAGL) is an enzyme of the endocannabinoid system, and is responsible for the degradation of the most abundant endocannabinoid in bone, 2-arachidonoyl glycerol (2AG).. The effects of the verified MAGL inhibitor on bone remodelling were assessed in healthy mice and in mouse models of bone disease caused by prostate and breast cancers and osteosarcoma.. JZL184 reduced osteolytic bone metastasis in mouse models of breast and prostate cancers, and inhibited skeletal tumour growth, metastasis and the formation of ectopic bone in models of osteosarcoma. Additionally, JZL184 suppressed cachexia and prolonged survival in mice injected with metastatic osteosarcoma and osteotropic cancer cells. Functional and histological analysis revealed that the osteoprotective action of JZL184 in cancer models is predominately due to inhibition of tumour growth and metastasis. In the absence of cancer, however, exposure to JZL184 exerts a paradoxical reduction of bone volume via an effect that is mediated by both Cnr1 and Cnr2 cannabinoid receptors.. MAGL inhibitors such as JZL184, or its novel analogues, may be of value in the treatment of bone disease caused by primary bone cancer and bone metastasis, however, activation of the skeletal endocannabinoid system may limit their usefulness as osteoprotective agents.

Topics: Animals; Benzodioxoles; Bone and Bones; Bone Neoplasms; Bone Remodeling; Bone Resorption; Cell Communication; Disease Models, Animal; Enzyme Inhibitors; Female; Heterografts; Humans; Mice; Monoacylglycerol Lipases; Osteoclasts; Osteolysis; Piperidines; Receptors, Cannabinoid

Topics: Adenine; Aged; Antineoplastic Agents; Calcification, Physiologic; Combined Modality Therapy; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Magnetic Resonance Imaging; Osteolysis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed; Treatment Outcome

Multiple myeloma (MM) cells typically grow in focal lesions, stimulating osteoclasts that destroy bone and support MM. Osteoclasts and MM cells are hypermetabolic. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is not only essential for cellular metabolism; it also affects activity of NAD-dependent enzymes, such as PARP-1 and SIRT-1. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin, encoded by PBEF1) is a rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide. Coculture of primary MM cells with osteoclasts induced PBEF1 upregulation in both cell types. PBEF1 expression was higher in experimental myelomatous bones than in nonmyelomatous bone and higher in MM patients' plasma cells than in healthy donors' counterparts. APO866 is a specific PBEF1 inhibitor known to deplete cellular NAD(+). APO866 at low nanomolar concentrations inhibited growth of primary MM cells or MM cell lines cultured alone or cocultured with osteoclasts and induced apoptosis in these cells. PBEF1 activity and NAD(+) content were reduced in MM cells by APO866, resulting in lower activity of PARP-1 and SIRT-1. The inhibitory effect of APO866 on MM cell growth was abrogated by supplementation of extracellular NAD(+) or NAM. APO866 inhibited NF-κB activity in osteoclast precursors and suppressed osteoclast formation and activity. PBEF1 knockdown similarly inhibited MM cell growth and osteoclast formation. In the SCID-rab model, APO866 inhibited growth of primary MM and H929 cells and prevented bone disease. These findings indicate that MM cells and osteoclasts are highly sensitive to NAD(+) depletion and that PBEF1 inhibition represents a novel approach to target cellular metabolism and inhibit PARP-1 and bone disease in MM.

Topics: Acrylamides; Animals; Bone and Bones; Cell Differentiation; Coculture Techniques; Cytokines; Enzyme Induction; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mice; Mice, SCID; Multiple Myeloma; NAD; Neoplasm Proteins; NF-kappa B; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Osteoclasts; Osteolysis; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Rabbits; Sirtuin 1; Tumor Cells, Cultured; Up-Regulation

Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17 nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5 nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Bone Marrow; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemokines; Coculture Techniques; Cytokines; Down-Regulation; Gene Expression; Humans; Immunoblotting; Mice; Mice, SCID; Multiple Myeloma; Osteoclasts; Osteolysis; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells; Tumor Microenvironment; Xenograft Model Antitumor Assays

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma.

Topics: Administration, Oral; Animals; Apoptosis; Biological Availability; Bone Matrix; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Clone Cells; Crizotinib; Humans; Mice; Mice, Nude; Neoplasm Invasiveness; Osteogenesis; Osteolysis; Osteosarcoma; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Xenograft Model Antitumor Assays

Multiple myeloma (MM) is a plasma cell malignancy, characterized by the localization of the MM cells in the bone marrow (BM), where they proliferate and induce osteolysis. The MM cells first need to home or migrate to the BM to receive necessary survival signals. In this work, we studied the role of CCR1 and CCR5, two known chemokine receptors, in both chemotaxis and osteolysis in the experimental 5TMM mouse model. A CCR1-specific (BX471) and a CCR5-specific (TAK779) antagonist were used to identify the function of both receptors. We could detect by RT-PCR and flow cytometric analyses the expression of both CCR1 and CCR5 on the cells and their major ligand, macrophage inflammatory protein 1alpha (MIP1alpha) could be detected by ELISA. In vitro migration assays showed that MIP1alpha induced a 2-fold increase in migration of 5TMM cells, which could only be blocked by TAK779. In vivo homing kinetics showed a 30% inhibition in BM homing when 5TMM cells were pre-treated with TAK779. We found, in vitro, that both inhibitors were able to reduce osteoclastogenesis and osteoclastic resorption. In vivo end-term treatment of 5T2MM mice with BX471 resulted in a reduction of the osteolytic lesions by 40%; while TAK779 treatment led to a 20% decrease in lesions. Furthermore, assessment of the microvessel density demonstrated a role for both receptors in MM induced angiogenesis. These data demonstrate the differential role of CCR1 and CCR5 in MM chemotaxis and MM associated osteolysis and angiogenesis.

Topics: Amides; Animals; Bone Marrow; Bone Resorption; CCR5 Receptor Antagonists; Cell Division; Cell Line, Tumor; Cell Movement; Chemokine CCL3; Chemokine CCL4; Chemokines, CC; Chemotaxis; Female; Macrophage Inflammatory Proteins; Mice; Mice, Inbred C57BL; Multiple Myeloma; Neoplasm Proteins; Neovascularization, Pathologic; Osteoclasts; Osteolysis; Phenylurea Compounds; Piperidines; Quaternary Ammonium Compounds; Receptors, CCR1; Receptors, CCR5; Receptors, Chemokine; Recombinant Fusion Proteins; Stromal Cells; Tumor Burden