The cyclooxygenase-2 Inhibitor NS-398 Inhibits Proliferation and Induces Apoptosis in Human Osteosarcoma Cells via Downregulation of the Survivin Pathway

Da-Peng Duan, Xiao-Qian Dang, Kun-Zheng Wang, Yong-Ping Wang, Hui Zhang, Wu-Lin You

Oncol Rep. 2012 Nov;28(5):1693-700.

PMID: 22922684

Abstract:

Cyclooxygenase-2 (COX-2) is frequently overexpressed in human malignancies and plays a crucial role in tumorigenesis and cancer progression. The present study aimed to investigate the expression and clinical significance of COX-2 and survivin (SUV) in human osteosarcomas (OS), and explore the effects and molecular mechanisms of a selective COX-2 inhibitor NS-398 and SUV on tumor proliferation and apoptosis. Fifty cases of human OS and osteochondromas (OC) were collected. The expression of COX-2 and SUV was assessed using immunohistochemical assays in biopsy samples. MG-63 human OS cells were treated with different concentrations of NS-398, used to investigate their effects on cell proliferation and apoptosis. The recombinant small hairpin RNA adenovirus vector rAd5-SUV was constructed, and the effects and molecular mechanisms of knockdown of SUV on proliferation and apoptosis were evaluated in MG-63 cells. A subcutaneous xenograft tumor model was established, validating the effects of rAd5-SUV on tumor growth in vivo. Based on the results, the expression of COX-2 and SUV in OS showed a higher strong reactivity rate compared with OC (73.3 vs. 25.0%, P=0.001; 63.3 vs. 30.0%, P=0.02), but it did not correlate with the clinicopathological characteristics of OS. NS-398 inhibited proliferation, induced apoptosis and decreased the mRNA expression of COX-2 and SUV in MG-63 cells. Furthermore, adenovirus-mediated knockdown of SUV inhibited proliferation, induced apoptosis, reduced the expression of proliferating cell nuclear antigen (PCNA), increased the expression of caspase-3 (CAS-3) and slowed the growth of xenograft tumors in MG-63 cells. Taken together, the expression of COX-2 and SUV is closely correlated with human OS, and inhibition of COX-2 or knockdown of SUV suppresses tumor proliferation and induces apoptosis, suggesting that COX-2 may be involved in OS cell proliferation and apoptosis through SUV-mediated regulation of PCNA and CAS-3 expression, and provides a potential therapeutic strategy for the treatment of cancer.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP123653112-B	NS-398 - CAS 123653-11-2		123653-11-2	Price