Cyclooxygenase-2 inhibitors induce anoikis in osteosarcoma via PI3K/Akt pathway. COX-2, an inducible enzyme, is associated with inflammatory diseases and carcinogenesis. Overexpression of COX-2 occurs in many human malignancies, including osteosarcoma. In our study, we reported that Celecoxib, a cyclooxygenase-2 inhibitor, induces apoptosis in human osteosarcoma cell line MG-63 via down-regulation of PI3K/Akt. PI3K/Akt plays an essential role in the cell/extracellar matrix (ECM) and cell/cell adhesion. We hypothesize that COX-2 inhibitors induce anoikis in osteosarcoma via PI3K/Akt, resulted in lack of correct attachment and the down-regulations of β-catenin, TrkB and E-cadherin, which play an essential role in the cell/extracellar matrix (ECM) and cell/cell adhesion. Meanwhile, apoptosis also be disclosed, such as DNA fragments and apoptotic bodies, activation of caspase-8, 9 and cleavage of PARP. With wortmannin, a specific PI3K inhibitor can simulate the effect of COX-2 inhibitors. If our hypothesis is correct, COX-2 inhibitors could cut down the occurrence of metastasis and facilitate the patient who may benefit from addition of COX-2 inhibitors to standard cytotoxic therapy.Copyright © 2012 Elsevier Ltd. All rights reserved.