title: Hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid on bone metastasis of lung cancer.
abstract: Hyaluronan is known to have pivotal roles in the growth, migration and invasion of malignant tumors. Bone metastases are critical lesions greatly impairing the quality of patients with malignancies. We investigated whether hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid, which is a conventional therapeutic agent for bone metastasis. We examined the effects of methylumbelliferone, an inhibitor of hyaluronan synthesis and/or ZA on the tumorigenicity of one murine lung carcinoma and two human (A549, SK-MES-1) lung cancer cell lines in vitro. The interaction between methylumbelliferone and zoledronic acid was analyzed using Calcucyn software. With a murine bone metastasis model of lung cancer in vivo, we investigated the inhibitory effects and interaction of the two drugs on the progression of metastatic bone lesions. Methylumbelliferone or zoledronic acid treatment individually suppressed proliferation, migration and invasion of 3 cell lines, and combination treatment showed synergistic effects. Although methylumbelliferone as a single agent did not enhance apoptotic activity, it showed additive effects on apoptotic activity to those of zoledronic acid. Co-localization of CD44 and ezrin, which might be a pathway of hyaluronan signaling, was abrogated by methylumbelliferone treatment. Combination therapy showed additive inhibitory effects on metastatic bone lesions in vivo, which paralleled the inhibition of hyaluronan accumulation by methylumbelliferone, and inhibition of osteoclastogenesis. Although the detailed mechanisms underlying the synergistic or additive inhibitory effects of these two drugs should be further analyzed, inhibition of hyaluronan synthesis by methylumbelliferone is a promising novel therapeutic candidate for bone metastasis of lung cancer in addition to zoledronic acid.
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65-Tsuruma, Showa, Nagoya, 466-8550, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Futamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Urakawa
authors.forename: Eisuke
authors.initials: E
authors.lastname: Arai
authors.forename: Eiji
authors.initials: E
authors.lastname: Kozawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D017931:DNA Primers; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077211:Zoledronic Acid
chemical_list: D017931:DNA Primers; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D006820:Hyaluronic Acid