Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation

Abstract

Abstract. Cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinase 1/2 (ERK1/2) may serve as potential targets in various types of cancer; however, the roles of these proteins in gallbladder carcinoma (GBC) have not been reported previously. In the present study, the expression levels of COX-2 and phospho (p)-ERK1/2 in GBC were examined and the biological activities of celecoxib and PD184161 (specific inhibitors of COX-2 and p-ERK1/2, respectively) on the proliferation, cell cycle and apoptosis of the GBC-SD and NOZ human GBC cell lines were evaluated by a series of in vitro and in vivo studies. COX-2 and p-ERK1/2 protein expression levels were found to be significantly elevated in GBC tissues as well as in GBC-SD and NOZ cells. Treatments with celecoxib and PD184161 significantly inhibited GBC-SD and NOZ cell growth in a concentration-dependent manner, and their combination produced a synergistic inhibitory effect. In addition, celecoxib and PD184161 significantly inhibited tumor growth in xenograft nude mice. Celecoxib treatment led to G1 arrest via the upregulation of p21 and p27 expression in GBC-SD and NOZ cells, whereas PD184161 did not affect cell cycle distribution. The combination of celecoxib and PD184161 was able to promote cell apoptosis by triggering a collapse of mitochondrial membrane potential and activating caspase-3-mediated apoptosis. In conclusion, COX-2 and p-ERK1/2 protein may serve as potential targets for GBC chemotherapy, and the combination of celecoxib and PD184161 could significantly inhibit GBC cell growth, induce cell G1 arrest and trigger cell apoptosis of GBC cells. IntroductionGallbladder carcinoma (GBC) is the most common malignancy of the biliary system and the fifth most common gastrointestinal cancer worldwide, with an annual incidence of >10,000 and mortality rate of ~3,300 individuals. Its morbidity varies with racial, ethnic and regional factors (1). In recent years, numerous studies have reported an increase in the incidence of GBC in certain areas, including north India, Pakistan and Korea (2,3). As the majority of GBC patients are diagnosed when the cancer has reached an advanced stage, they have an extremely poor prognosis, with a median 5-year survival rate of 2-5% (4). Chemotherapy is considered to be the most valuable treatment to prolong the survival time and improve the quality of life of these patients. However, GBC shows resistance to the majority of currently used chemotherapeutic agents, and the real clinical effect of such agents is unsatisfactory (5). With rapid developments in cancer molecular and cell biology, targeted cancer therapies, which are drugs that interfere with specific molecules involved in cancer cell growth and survival, bring new hope for cancer patients. The growth and development of most tumors involves multiple genetic abnormalities, which diminishes the antitumor activities of the majority of single-targeted drugs in clinical applications. To date, GBC clinical trials have demonstrated that most single-targeted drugs for GBC ha...

Associations between serum uric acid and hepatobiliary-pancreatic cancer: A cohort study

“…Xie et al[ 35 ] conducted an in vitro experiment examining the effect of COX-2 on the angiogenesis of pancreatic cancer cells and indicated that COX-2 was positively associated with the microvascular density, promoting pancreatic cancer cell growth. Celecoxib, a selective COX-2 inhibitor, was found to enhance the effect of chemotherapeutic drugs on pancreatic cancer and inhibit the proliferation of gallbladder cancer cells[ 36 , 37 ]. Ohtsubo et al[ 38 ] confirmed that SUA regulates the expression of COX-2 through XOR in in vivo and in vitro experiments, which may explain the association between SUA and cancer.…”

Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico

“…Not surprisingly, expression levels of certain miRNA strands in vitro significantly enhanced GBC proliferation and invasion [ 51 ]. The strong associations discussed above argue that there may be a role for anti-inflammatory agents in the prevention or treatment of GBC [ 52 , 53 ]. Population studies have indicated that the use of aspirin, an inhibitor of COX-2 protein, may reduce the risk of GBC (OR 0.37) [ 54 ].…”

“…Population studies have indicated that the use of aspirin, an inhibitor of COX-2 protein, may reduce the risk of GBC (OR 0.37) [ 54 ]. Several in vitro studies have been performed attempting to treat GBC with various anti-inflammatory agents with promising results [ 52 ], but there have been no human trials to date.…”

Non-Steroidal Anti-Inflammatory Drugs Increase Cisplatin, Paclitaxel, and Doxorubicin Efficacy against Human Cervix Cancer Cells

“…The anti-cancer effects of celecoxib are associated with the following: (i) the inhibition of the highly over-expressed tumor cyclooxygenase-2 (COX-2), which in turn has been related to the acquisition and maintenance of an invasive metastatic phenotype [ 14 ]; (ii) the activation of the intrinsic apoptosis pathway [ 15 ]; (iii) the inhibition of oxidative phosphorylation (OxPhos) [ 12 , 13 ]; and (iv) the blocking of cell migration and invasiveness [ 12 ]. The combination of celecoxib with some drugs (PD184161, ZD6474, or plumbagin) has been already successfully tested on several carcinomas (gallbladder cancer, osteosarcoma, melanoma) [ 16 , 17 , 18 ]. However, some of these latter drugs are currently still under development, and they have not yet been approved by the USA Food and Drug Administration, which will most likely delay their eventual entry into the clinic [ 19 , 20 ].…”