ABSTRACT
Osteoclasts are formed from the monocyte-macrophage lineage in response to receptor activator of nuclear factor kappaB ligand (RANKL) expressed by osteoblasts. Bone is the most common site of breast cancer metastasis, and osteoclasts play roles in the metastasis. The taxane-derived compounds paclitaxel and docetaxel are used for the treatment of malignant diseases, including breast cancer. Here we explored the effects of docetaxel on osteoclastic bone resorption in mouse culture systems. Osteoclasts were formed within 6 days in cocultures of osteoblasts and bone marrow cells treated with 1,25-dihydroxyvitamin D(3) plus prostaglandin E(2). Docetaxel at 10(-8) M inhibited osteoclast formation in the coculture when added for the entire culture period or for the first 3 days. Docetaxel, even at 10(-6) M added for the final 3 days, failed to inhibit osteoclast formation. Osteoprotegerin, a decoy receptor of RANKL, completely inhibited osteoclast formation when added for the final 3 days. Docetaxel at 10(-8) M inhibited the proliferation of osteoblasts and bone marrow cells. RANKL mRNA expression induced by 1,25-dihydroxyvitamin D(3) plus prostaglandin E(2) in osteoblasts was not affected by docetaxel even at 10(-6) M. Docetaxel at 10(-6) M, but not at 10(-8) M, inhibited pit-forming activity of osteoclasts cultured on dentine. Actin ring formation and L: -glutamate secretion by osteoclasts were also inhibited by docetaxel at 10(-6) M. Thus, docetaxel inhibits bone resorption in two different manners: inhibition of osteoclast formation at 10(-8) M and of osteoclast function at 10(-6) M. These results suggest that taxanes have beneficial effects in the treatment of bone metastatic cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Bone Resorption , Bone and Bones/drug effects , Osteoclasts/drug effects , Osteoclasts/physiology , Taxoids/pharmacology , Actins/metabolism , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/physiology , Bone and Bones/cytology , Bone and Bones/physiology , Calcitriol/metabolism , Cell Survival/drug effects , Cells, Cultured , Coculture Techniques , Dinoprostone/metabolism , Docetaxel , Glutamic Acid/metabolism , Humans , Macrophages/cytology , Macrophages/drug effects , Macrophages/physiology , Male , Mice , Osteoblasts/cytology , Osteoblasts/physiology , Osteoclasts/cytology , Paclitaxel/pharmacology , RANK Ligand/genetics , RANK Ligand/metabolismABSTRACT
AIM: Inorganic polyphosphate exists as chains of phosphate molecules and is distributed in osteoblasts, and regulates osteoblastic cell differentiation and bone matrix calcification. The purpose of this study was to clarify the effects of inorganic polyphosphate on periodontitis. MATERIAL AND METHODS: Subgingival local irrigation with inorganic polyphosphate was studied in a randomised double-blind study of 33 patients with periodontitis. Scaling and root planing were performed 1 week after the initial examination. RESULTS: No significant differences between the inorganic polyphosphate group and control were detected in each item except IL-1beta. Patients in whom both the bleeding on probing and gingival index at 1 week had improved were significantly older in the inorganic polyphosphate group than in the control group (p < 0.05). Bone regeneration was seen in one case of the inorganic polyphosphate group. CONCLUSIONS: Inorganic polyphosphate was useful in the treatment of periodontitis in the elderly, indicating a probable effect of anti-ageing, with similar bone regenerations occurring in both groups.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Dental Care for Aged/methods , Periodontitis/drug therapy , Polyphosphates/therapeutic use , Adult , Aged , Aged, 80 and over , Aging/drug effects , Anti-Inflammatory Agents/pharmacology , Bone Regeneration/drug effects , Dental Scaling , Double-Blind Method , Female , Gingival Crevicular Fluid/chemistry , Humans , Interleukin-1alpha/biosynthesis , Male , Middle Aged , Periodontitis/metabolism , Polyphosphates/pharmacologyABSTRACT
The aim of the present study was to clarify whether ATP binding cassette transporters are refractory factors in head and neck cancers. For in vitro and in vivo chemotherapeutic studies, we used the following head and neck cancer cell lines: a mouse oral squamous cell carcinoma (SCC) cell line, Sq-1979; a human SCC cell line, SCCHA; a mouse salivary gland adenocarcinoma (SGA) cell line, NR-PG; and a human SGA cell line, HSY. We used a vinca alkaloid anticancer drug, vincristine (VCR), as a chemotherapeutic anticancer drug. To determine the cause of multidrug resistance, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry of xenografted tumors in nude mice, drug efflux analysis, and drug efflux inhibitory assays were performed. VCR-treated cell lines, Sq-1979/VCR, SCCHA/VCR, NR-PG/VCR, and HSY/VCR, intensively expressed multidrug resistance (MDR) gene 1 mRNA and multidrug resistance associated protein (MRP) 1 mRNA. MRP7 mRNA and protein were expressed in NR-PG/VCR and HSY/VCR cells, but not in Sq-1979/VCR and SCCHA/VCR cells. In each cell clone of NR-PG/VCR and HSY/VCR, MRP7 mRNA was induced by VCR treatment, suggesting an acquired resistance to VCR in the context of MRP7 expression. In the in vivo chemotherapeutic nude mice model, VCR-treated xenografted SCCHA and HSY cells expressed MDR1 and MRP1. Moreover, MRP7 expression was immunohistochemically found in xenografted HSY cells of VCR-injected tumor-bearing mice, but not in SCCHA cells. Furthermore, doxorubicin accumulation was increased and drug cross-resistance to docetaxel decreased in HSY/VCR in the presence of a competitive MRP7 inhibitor, 17-beta-estradiol-(17-beta-D-glucuronide). These results indicate that MDR1 expression, MRP1 expression, and MRP7 expression are refractory factors in head and neck cancer chemotherapy and suggest that induction of MRP7 expression is involved in drug resistance to natural products, especially to docetaxel in SGA.
