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Carcinogenesis Advance Access published online on October 11, 2005
Carcinogenesis, doi:10.1093/carcin/bgi240
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received June 15, 2005
Revised September 24, 2005
Accepted September 30, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Meloxicam inhibits osteosarcoma growth, invasiveness and metastasis by COX-2-dependent and independent routes

Takahiro Naruse 1, Yoshihiro Nishida 1*, Kozo Hosono 1, and Naoki Ishiguro 1

1 Department of Orthopedic Surgery, Nagoya University School and Graduate School of Medicine, 65 Tsurumai-cho, Showa, Nagoya 466-8550, Japan

* To whom correspondence should be addressed.
Yoshihiro Nishida, E-mail: ynishida{at}med.nagoya-u.ac.jp


  Abstract

COX-2 inhibitors exert antitumor activity via COX-2-dependent and independent pathways. We wished to evaluate the antitumor activity of meloxicam, a preferential COX-2 inhibitor, in osteosarcoma, the most common primary malignant bone tumor, and determine whether its antitumor effect is COX-2-dependent. COX-2 expression in the osteosarcoma cell lines MG-63, HOS, and U2-OS was determined by real-time RT-PCR and Western blotting. Subsequently, the inhibitory effects of meloxicam on osteosarcoma cell growth and invasiveness were assayed by MTT and matrigel invasion assays, respectively. Apoptotic activity was evaluated by TUNEL staining and semi-quantitation of Bax and Bcl-2 expression by real time RT-PCR and Western blotting. PGE2 production in the presence and absence of meloxicam was analyzed by EIA, and to determine whether the effects of meloxicam are COX-2-dependent or independent, PGE2 was added to see if it reversed the effects of meloxicam. In addition, the effects of meloxicam on tumor growth and metastasis were evaluated in an in vivo mouse model using grafted LM-8 mouse osteosarcoma cells, together with immunohistochemical analysis for VEGF in lung metastatic lesion. Meloxicam inhibited PGE2 production, proliferation and invasiveness especially in MG-63 cells, which express relatively high levels of COX-2. Only high concentrations of meloxicam caused apoptosis and up-regulated Bax mRNA and protein in MG-63 cell culture. In contrast, meloxicam did not induce apoptosis in HOS and U2-OS cells, expressing relatively low levels of COX-2. Exogenous PGE2 reduced the effects of meloxicam on cell viability and invasiveness, but not its effect on Bax mRNA. In vivo, high doses of meloxicam suppressed LM-8 tumor growth and lung metastasis. Meloxicam, may have both COX-2-dependent and independent inhibitory actions on osteosarcoma. Its effects are more prominent in osteosarcoma cells that have relatively high levels of COX-2.

Keywords: COX-2; osteosarcoma; meloxicam; cancer; PGE2.
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