| Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. With current therapies of OS, such as extensive surgical excision, radiotherapy and neoadjuvant chemotherapy, five-year survival rate has increased up to 50%-60%. Platinum-based drugs, such as cisplatin, are an important class of the most active chemotherapeutic agents that are widely used to OS. Cisplatin cytotoxicity involves the formation of intra and interstrand DNA adducts, and the resulting DNA damage triggers apoptosis.The cyclooxygenase (COX) isoenzymes known as a prostaglandins (PGs) ratelimiting synthase catalyze the metabolism of arachidonic acid to PGs. Three isoforms of COX isoenzymes have been identified: COX-1, COX-2, and COX-3. COX-1 is considered a "housekeeping enzyme", constitutively expressed in human cells. COX-3, an alternate splice variant of COX-1, is most abundant in the canine cerebral cortex. COX-2 is an inducible enzyme and is associated with inflammatory diseases and carcinogenesis. The activity of COX-2 is suspected to promote angiogenesis and tissue invasion of tumors and COX-2 over-expression has been mentioned in connection with resistance to apoptosis. Over-expression of COX-2 has been found in many human malignancies, such as colorectal, liver, pancreatic, breast, lung tumors and osteosarcoma. Thus selective pharmacologic inhibition of COX-2 represents a viable therapeutic option for the treatment of malignancies.Nonsteroidal anti-inflammatory drugs (NSAIDs) are COX inhibitors that have been shown to induce apoptosis as well as potentialize the effects of chemotherapeutic agents including cisplatin in vitro and in vivo experimental studies. Consistent with the anti-apoptotic effect of COX-2, induction of cancer cell apoptosis is the principle mechanism by which NSAIDs inhibit cancer cell growth. Celecoxib is a new generation of NSAIDs that specifically inhibits COX-2 activity .Although the precise mechanisms of celecoxib are not yet known, the inhibition of cell proliferation and the induction of apoptosis have been well-known, which have been confirmed in colorectal tumors and familial adenomatous polyposis (FAP). Celecoxib induces apoptosis through COX-2-dependent and -independent pathways. So we exert celecoxib and cisplatin to osteosarcoma cell in vivo and detect the effects of the combination or each agent alone.Cyclooxygenase-2 (COX-2), involved in the inhibition of cell apoptosis and the potentiation of cell growth, is frequently overexpressed in human malignancies including osteosarcoma (OS).We have attempted to identify the anti-proliferation of celecoxib, a selective COX-2 inhibitor, and the combination of celecoxib and cisplatin in MG-63 cells, and to explore the potential molecular mechanisms involved.MG-63 cells were treated with the combination of celecoxib and cisplatin or either agent alone for 48 h in serum-supplemented medium. Celecoxib caused G1 phase arrest and significantly inhibited cell growth, as well as potentiating cisplatin-induced apoptosis. The effect was dose-dependent, and apoptotic changes such as DNA fragments and apoptotic bodies were observed.However, downregulation of COX-2 did not occur in cells treated with celecoxib. Phosphoinositide-3-kinase(PI3K)/Akt, survivin, bcl-2 were significantly downregulated in cells treated with the combination of celecoxib and cisplatin, and decreased survivin and bcl-2 levels were found in cells with wortmannin, a specific PI3K inhibitor. Moreover, the decreased expressions of procaspase-9, procaspase-3 and cleaved PARP-1 were detected by Western blot analysis. Therefore, celecoxib exerts its anti-tumor activities through COX-2-independent mechanisms, which may be PI3K/Akt-dependent, and survivin and bcl-2-related. PI3K may be at the center of the celecoxib effects, which play an essential role in the regulation of survivin and Bcl-2.
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