Cyclooxygenase-2 inhibitor celecoxib suppresses invasion and migration of nasopharyngeal carcinoma cell lines through a decrease in matrix metalloproteinase-2 and -9 activity.

Celecoxib is a selective inhibitor of COX-2, whose connection with the development and progression of human tumors has been extensively studied. So far, however, its anti-metastatic effect is poorly understood in nasopharyngeal carcinoma. The current study aimed to observe the effect of celecoxib on invasion and migration of nasopharyngeal carcinoma cell lines and investigate the potential mechanism in vitro. Human nasopharyngeal carcinoma cell lines HNE1, HONE1, SUNE1-5-8F were exposed to different concentrations of celecoxib. MTT assay was used to study its anti-proliferation effect, transwell assay wound healing repair assay were performed to investigate the invasiveness and migration capability after treatment with celecoxib. The activity of MMP-2 and MMP-9 was measured by gelatin zymography. MTT assay showed that celecoxib inhibited HNE1, HONE1, and SUNE1-5-8F cells growth. Wound healing repair assay and transwell assay showed that cell metastatic ability was suppressed after treatment with celecoxib. Celecoxib had a significant inhibitory effect on the activity of MMP-2/9 in a dose-dependent manner in HNE1, HONE1 and SUNE1-5-8F cell lines. These data demonstrated that celecoxib-induced suppression of MMP-2 and MMP-9 activity might be involved in the inhibition of nasopharyngeal carcinoma cell lines invasion and migration.

Anticancer effects of celecoxib through inhibiton of STAT3 phosphorylation and AKT phosphorylation in nasopharyngeal carcinoma cell lines.

Previously, we showed that treatment with celecoxib obviously inhibited proliferation of nasopharyngeal carcinoma (NPC) cell lines in a dose-dependent manner. However, the underlying molecular mechanisms of its anticancer effect on NPC have not been fully clarified. The present in vitro study was performed to investigate the mechanisms involved in the anticancer effect of celecoxib in NPC. NPC cell line HONE1 was treated with celecoxib at varying concentrations. The antiproliferation effect of celecoxib on the HONE1 cell line was assessed with methyl thiazolyl tetrazolium (MTT) assay. Western blot analysis of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3(Y705) (pSTAT3(Y705)), Survivin, Mcl-1, Bcl-2 and Cyclin D1 was carried out at various concentration of celecoxib for 48 h in HONE1 cell line. Western blot analysis of Protein Kinase B (AKT), phosphorylated AKT (pAKT) was performed at increasing doses of celecoxib for 48 h in HNE1, CNE1-LMP1 and HONE1 cells. The results showed that celecoxib inhibited proliferation of HONE1 cell line in a dose-dependent manner. Celecoxib inhibited the activation of STAT3 phosphorylation in HONE1 cells and the downstream genes of STAT3 (Survivin, Mcl-1, Bcl-2 and Cyclin D1) were downregulated after treatment with celecoxib. Furthermore, celecoxib could inhibit AKT phosphorylation in HNE1, CNE1-LMP1 and HONE1 cell lines. These data suggested that celecoxib was a promising agent for the chemoprevention and treatment of NPC.

Metabolic-induced cytotoxicity of diosbulbin B in CYP3A4-expressing cells.

As a candidate antitumor agent, diosbulbin B (DB) can induce serious liver toxicity and other adverse reactions. DB is mainly metabolized by CYP3A4 in vitro and in vivo, but the cytotoxicity and anti-tumor mechanisms of DB have yet to be clarified. This study aimed to determine whether the cytotoxicity and anti-tumor effects of DB are related to the metabolism-induced activation of CYP3A4 in various cell models, including CYP-free NIH3T3 cells, primary rat hepatocytes, HepG2 and L02 cells of high CYP3A4 expression and wild-type. Results showed that DB did not markedly decrease the viability of NIH3T3 cells. DB metabolites, obtained from the metabolism by mouse liver microsomes, did not elicit cytotoxicity on NIH3T3 cells either. By contrast, DB could induce significant cytotoxicity on primary rat hepatocytes. The DB induced cytotoxicity on HepG2 or L02 cells with high CYP3A4 expression were stronger than those on wild-type cells. As a metabolic biomarker, the metabolite conjugate (M31) of DB with GSH was detected in the incubation system. A higher amount of M31 was generated in the transfected HepG2 and L02 cells than in the wild-type cells at different time points. Ketoconazole, however, could restrain DB induced cytotoxicity on primary rat hepatocytes and in CYP3A4 transfected HepG2 and L02 cells. Therefore, the cytotoxicity of DB was closely related to CYP3A4-metabolized reactive DB metabolites.