Anti-cancer Effects Of Celecoxib Research Articles

N-acetyl-cysteine in combination with celecoxib inhibits Deoxynivalenol induced skin tumor initiation via induction of autophagic pathways in swiss mice

Deoxynivalenol is a trichothecene mycotoxin which naturally contaminates small grain, cereals intended for human and animal consumption. Investigations for dermal toxicity of DON has been needed and highlighted by WHO. Previous studies on dermal toxicity suggest that DON has DNA damaging potential leading to skin tumor initiation in mice skin. However, considering its toxicological manifestations arising after dermal exposure, strategies for its prevention/protection are barely available in literatute. Collectively, our study demonstrated that N-acetylcysteine (NAC), precursor of glutathione, significantly alters the genotoxic potential of DON. Further NAC in combination with Celecoxib (CXB) inhibits tumor growth by altering antioxidant status and increasing autophagy in DON initiated Swiss mice. Despite the broad spectrum use of CXB, its use is limited by the concerns about its adverse effects on the cardiovascular system. Serum parameters and histology analysis revealed that CXB (2 mg) when applied topically for 24 weeks did not impart any cardiovascular toxicity which could be because skin permeation potential of CXB was quite low when analyzed through HPLC analysis.Although the anticancer effects of CXB and NAC have been studied, however, the combination of NAC and CXB has yet not been explored for any cancer treatment. Therefore our observations provide additional insights into the therapeutic effects of combinatorial treatment of CXB and NAC against skin tumor prevention. This approach might form a novel alternative strategy for skin cancer treatment as well as skin associated toxicities caused by mycotoxins such as DON. This combinatorial approach can overcome the limitations associated with the use of CXB for long term as topical application of the same seems to be safe in comparison to the oral mode of administration.

The synergistic effect between celecoxib and luteolin and dependence on estrogen receptor in human breast cancer cells.

135 Background: The anti-cancer effects of celecoxib and luteolin are well known. Although our previous study demonstrated that the combination of celecoxib and luteolin synergistically inhibits breast tumor growth compared with each of the treatments alone, we did not uncover the molecular mechanisms of these effects. The aims of our present study were to compare the effects of a celecoxib and luteolin combination treatment in four different human breast cell lines and to determine the mechanisms of action in vitro and in vivo. Methods: Using MCF-7, MCF7/HER18, MDA-MB-231 and SkBr3 human breast cancer cells, proliferation assay, apoptosis assay, inhibition assay with MEK and PI3K inhibitor in addition to western blotting and xenograft study after treatment with celecoxib and luteolin. Results: The synergistic effects of a celecoxib and luteolin combination treatment yielded significantly greater cell growth inhibition in all four breast cancer cell lines compared with the single agents alone. In particular, combined celecoxib and luteolin treatment significantly decreased the growth of MDA-MB-231 cancer cells in vivo compared with either agent alone. The celecoxib and luteolin combination treatment induced synergistic effects via Akt inactivation and extracellular signal-regulated kinase (ERK) signaling inhibition in MCF-7 and MCF7/HER18 cells and via Akt inactivation and ERK signaling activation in MDA-MB-231 and SkBr3 cells. Conclusions: These results demonstrate the synergistic anti-tumor effect of the celecoxib and luteolin combination treatment in different four breast cancer cell lines, thus introducing the possibility of this combination as a new treatment modality.

2,5-Dimethyl-celecoxib inhibits cell cycle progression and induces apoptosis in human leukemia cells.

Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies.

Synergistic effect between celecoxib and luteolin is dependent on estrogen receptor in human breast cancer cells.

The anti-cancer effects of celecoxib and luteolin are well known. Although our previous study demonstrated that the combination of celecoxib and luteolin synergistically inhibits breast tumor growth compared with each of the treatments alone, we did not uncover the molecular mechanisms of these effects. The aims of our present study were to compare the effects of a celecoxib and luteolin combination treatment in four different human breast cell lines and to determine the mechanisms of action in vitro and in vivo. The synergistic effects of a celecoxib and luteolin combination treatment yielded significantly greater cell growth inhibition in all four breast cancer cell lines compared with the single agents alone. In particular, combined celecoxib and luteolin treatment significantly decreased the growth of MDA-MB-231 cancer cells in vivo compared with either agent alone. The celecoxib and luteolin combination treatment induced synergistic effects via Akt inactivation and extracellular signal-regulated kinase (ERK) signaling inhibition in MCF-7 and MCF7/HER18 cells and via Akt inactivation and ERK signaling activation in MDA-MB-231 and SkBr3 cells. These results demonstrate the synergistic anti-tumor effect of the celecoxib and luteolin combination treatment in different four breast cancer cell lines, thus introducing the possibility of this combination as a new treatment modality.

Hedgehog-glioma-associated oncogene homolog-1 signaling in colon cancer cells and its role in the celecoxib-mediated anti-cancer effect.

Hedgehog (Hh) signaling is activated in numerous malignant tumors, but its role in human colorectal cancer remains uncertain. Celecoxib, a selective cyclooxygenase-2 inhibitor, has been shown to exhibit chemoprevention in colorectal cancer, however, the effects of celecoxib on Hh signaling remain unknown. The current study presents an evaluation of Hh signaling in colon cancer cell lines and the effects of celecoxib in vitro. Active Hh signaling was observed in LoVo and HT-29 cells, with particularly high levels in the LoVo cells. However, Hh signaling activity was absent in HCT-116 cells. Quantitative polymerase chain reaction indicated that the expression of Hh receptor patched homolog 1 (PTCH1) was absent in the LoVo cells, but that they exhibited high levels of glioma-associated oncogene homolog-1 (GLI1) expression, while high expression levels of PTCH1 and low expression levels of smoothened (SMO) and GLI1 were observed in the HCT-116 cells. The HCT-116 cells were extremely sensitive to celecoxib, whereas the LoVo cells were resistant to the anticancer effect of the drug. Celecoxib downregulated the expression of GLI1 in the HCT-116 and HT-29 cells, but did not change the expression of GLI1 in the LoVo cells. The results presented in this study indicated that the anticancer effect of celecoxib is selective in colon cancer cells; celecoxib may target cancer cells via the SMO-independent modulation of GLI1 activity, and Hh signaling may be significant in maintaining the malignant state of LoVo cells. These findings may aid in improving our understanding of the carcinogenesis of colon cancer and the development of novel approaches for the targeted therapy of this disease.

Celecoxib Inhibits Interleukin-6/Interleukin-6 Receptor–Induced JAK2/STAT3 Phosphorylation in Human Hepatocellular Carcinoma Cells

Growing evidence shows an association between chronic liver inflammation and hepatocellular carcinoma (HCC) development. STAT3, which is associated with inflammation and cellular transformation, is constitutively activated in human HCC tissues but not in normal human liver tissues. Although interleukin-6 (IL-6) is elevated in the serum of patients with HCC, it is not fully understood whether STAT3 constitutive activation is positively correlated with autocrine IL-6 secreted by HCC cells. Here, we reported that in HCC cells, the elevated levels of both IL-6 and IL-6 receptor (IL-6R, gp80), not IL-6 alone, correlated with STAT3 activation. We also explored whether the anticancer effects of celecoxib, an anti-inflammatory drug, may be due to the inhibition of the IL-6/STAT3 pathway in HCC cells. Our results showed that celecoxib decreased STAT3 phosphorylation by reducing Janus-activated kinase (JAK2) phosphorylation and caused apoptosis in HCC cells. Celecoxib could also block exogenous IL-6-induced STAT3 phosphorylation and nuclear translocation. Moreover, we observed more significant inhibition of cell viability when celecoxib was combined with doxorubicin or sorafenib. We conclude that the elevated levels of IL-6/IL-6R may be correlated with STAT3 activation in HCC cells. Celecoxib may be a candidate for HCC therapy through blocking IL-6/STAT3 pathway and can be combined with other anticancer drugs to reduce drug resistance caused by IL-6/STAT3 signals.

Role of leukotriene B 4 in celecoxib-mediated anticancer effect

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has anticancer effect on many cancers associated with chronic inflammation by both COX-2-dependent and COX-2-independent mechanisms. The non-COX-2 targets of celecoxib, however, are still a matter of research. Leukotriene B 4 (LTB 4) has been implicated in prostate and colon carcinogenesis, but little is known about the potential role of LTB 4 in celecoxib-mediated anticancer effect. In this study, we evaluated whether LTB 4 was involved in celecoxib-mediated inhibitory effect on human colon cancer HT-29 cells and human prostate cancer PC-3 cells. Our data showed that survival of both cell lines was obviously suppressed after celecoxib treatment for 72 h in a concentration-dependent manner. However, only in HT-29 cells, this inhibitory effect could be reversed by LTB 4, which promoted survival of HT-29 cells rather than PC-3 cells. Consistent with these results, lioxygenase (LOX) potent inhibitor nordihydroguaiaretic acid (NDGA) had a higher inhibitory effect on HT-29 cells than PC-3 cells. Additionally, ELISA results showed that celecoxib could suppress expression of LTB 4 in both cell lines, whereas, inhibition of PGE 2 was only detected in HT-29 cells. These results indicate that the anticancer effect of celecoxib is COX-2-independent in HT-29 and PC-3 cells and in HT-29 cells primarily via down-regulating LTB 4 production.

Anti-cancer effect of celecoxib and aerosolized docetaxel against human non-small cell lung cancer cell line, A549

Direct delivery of chemotherapeutic agents to the lung can increase both the drug concentration and exposure period to lung tumours. The objective of this study was to formulate docetaxel (DOC) into a metered dose inhaler (MDI), assess its aerodynamic characteristics and to evaluate the effect of celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, on the in-vitro cytotoxicity and apoptotic response of aerosolized DOC against human lung adenocarcinoma cell line A549. A stable solution-type MDI formulation was developed with 0.25% DOC and 15% w/w ethyl alcohol using HFA 134a propellant. The formulation was evaluated for medication delivery, mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), percent throat deposition, respirable mass and respirable fraction. A six-stage viable impactor was used to assess the in-vitro cytotoxicity of DOC-MDI alone or in combination with CXB. Induction of apoptosis in A549 cells by DOC (non-aerosolized and aerosolized) in combination with CXB was evaluated by established techniques, such as caspase-3 estimation and terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) staining. The influence of different treatments on the expression of COX-2 and peroxisome proliferator-activated receptor-gamma(PPAR-gamma) in A549 cells was studied by RT-PCR. The DOC-MDI formulation had a MMAD of 1.58 microm, (GSD = 3.2) and a medication delivery of 80 microg/shot. DOC-MDI (one shot) in combination with CXB (10 microg mL(-1)) had a cell kill of more than 80% as determined by in-vitro cytotoxicity assay. The specific caspase-3 activity in A549 cells treated with DOC (0.01 microg mL(-1)) and CXB (10.0 microg mL(-1)) combination was 4 times higher than CXB and untreated control group, respectively. Further, TUNEL staining showed significant apoptosis of A549 cells treated with aerosolized DOC alone or in combination with CXB when compared with CXB and untreated cells. The RT-PCR experiments showed similar expression of COX-2 in both control and treated groups. PPAR-gamma expression was increased in the combination treatment (0.01 microg mL(-1) DOC and 10 microg mL(-1) CXB) as compared with control (untreated), DOC (0.01 microg mL(-1)) and CXB (10 microg mL(-1)) treatments. Our results indicate the potential of inhalation delivery of DOC in the treatment of lung cancer.

Anti-cancer effects of celecoxib in head and neck carcinoma.

Although many studies highlighted cyclooxygenase2 (COX2) inhibition as a promising therapeutic strategy for cancer, more evidence is needed for clinical application. The purpose of this study was to investigate the feasibility of COX2 inhibition as a strategic treatment modality for head and neck carcinoma (HNC). We tested COX2 inhibitor, celecoxib in six types of HNC cells and analyzed the expression changes in proteins related to angiogenesis and apoptosis in vitro. We also evaluated proliferation, gelatinolysis and in vitro invasion. We used a hamster carcinogenesis model and a mouse tumorigenesis model for the in vivo evaluation of COX2 inhibition. We performed immunohistochemistry to assess changes in the expression of COX2, survivin and angiogenesis. Celecoxib administration caused decreases in the expressions of COX2, VEGF and survivin in vitro. Proliferation, in vitro invasion and gelatinolytic activity were reduced in HNC cell lines, but the effect was inconsistent across lines. COX2 inhibition retarded oral carcinogenesis from an early carcinogenic stage with increased apoptosis and decreased survivin expression. COX2 inhibition did not inhibit tumor growth, even with the COX2 downregulation and decrease in neovascularization. We conclude that COX2 inhibition has a chemopreventive effect, but its application as a treatment of HNC in a clinical setting still requires further research to overcome its limited anti-cancer effects.

Anticancer Effect of Celecoxib via COX-2 Dependent and Independent Mechanisms in Human Gastric Cancers Cells

Cyclooxygenase-2 (COX-2) inhibitors cause growth inhibition of human gastric carcinoma cells, but it remains unclear whether this is both COX-2 dependent and independent. The related mechanisms remain to be determined. Both low COX-2 expressing gastric carcinoma and high COX-2 expressing gastric carcinoma cells were used to study the effect and mechanisms of celecoxib on gastric carcinoma cell growth. Celecoxib resulted in comparable growth inhibition in AGS cells with stable transfections of small interfering RNA (siRNA) against COX-2 (SAC) and negative control vector (NC) cells. Simultaneously, celecoxib resulted in significant reduction of Bcl-2 and significant increase of p21(WAF1) and p27(KIP1) in SAC and NC cells. The present study shows that celecoxib causes growth inhibition of gastric carcinoma cells by decreasing Bcl-2 of cyclooxygenase-2-dependent pathway, and by increasing p21(WAF1) and p27(KIP1) of cyclooxygenase-2-independent pathway. These data extend our knowledge on the effect and mechanisms of celecoxib-induced inhibition of gastric carcinoma cell growth.

Potent cell growth inhibitory effects in hepatitis B virus X protein positive hepatocellular carcinoma cells by the selective cyclooxygenase‐2 inhibitor celecoxib

Hepatitis B virus (HBV) X protein (HBx) and cyclooxygenase-2 (COX-2) are all playing roles in hepatocellular carcinoma (HCC), but the reversing effects of COX-2 inhibitors on the neoplastic features caused by HBx protein is still unclear. To further evaluate the therapeutic potential of celecoxib on HBx mediated transformation, HCC cells transfected with HBx gene were treated with COX-2 selective inhibitor, celecoxib. The amount the main metabolite of COX-2, prostaglandin E2 (PGE2), was determined by using high sensitivity ELISA. Electron microscope and flow cytometry was used to analyze cell apoptosis and cell cycle distribution. RT-PCR and Western blot were used to identify the molecules involved in celecoxib induced cell apoptosis. The results showed that celecoxib inhibited cell growth more significantly and also induced more cell apoptosis in HBx over-expression cells than in control cells. Celecoxib could selectively inhibited COX-2 expression and PGE2 production. Celecoxib also inhibited p(473Ser)Akt, raf and p53 expression, and induced apoptosis by release of cytochrome c and activation of caspase 9, 3, and 6, which were more remarkably in HBx positive cells than in control cells. These results suggest that celecoxib had potent cell growth inhibitory effects on HBx positive HCC cells mainly through inducing more cell apoptosis, and these findings provide a new insight into the anticancer effects of celecoxib against HBx related HCC.

M1641 Anti-Gastric Cancer Effect of Celecoxib, a Selective COX-2 Inhibitor, Through Inhibition of AKT Signaling

Background and Aim: Previously, we showed that treatment with celecoxib significantly reduced the number of viable gastric cancer cells, in a dose- and time-dependent manner. However, the specific anti-cancer effects of celecoxib on gastric cancer cells have not been clarified. The present in vitro study was carried out to investigate the mechanism involved in the anti-gastric cancer effects of celecoxib. Methods: 3-(4,5-Dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was carried out after treating AGS cells (human gastric cancer cell line, ATCC CRL 1739) with celecoxib or indomethacin, and the effect of prostaglandin E2 or LY294002 (PI3K inhibitor) was evaluated. Western blot analysis of tAkt (total Akt), pAkt (phosphorylated Akt), pGSK3b (phosphorylated glycogen synthase kinase-3b), pFKHR (phosphorylated forkhead transcriptional factor), and caspase-9 was carried out at various concentrations (0, 5, 10, 25, or 50 mmol/L) of celecoxib or indomethacin-treatment for 24 or 48 h in AGS cells. Results: Celecoxib- or LY294002-induced cell death was found to occur in a dose- dependent manner in AGS cells, and these decreases were slightly recovered by the addition of PGE2 (25 or 50 mmol/L). The expression of pAkt but not tAkt was lower in the celecoxib treated-AGS cells and the response was dose dependent (P < 0.05). The expres- sion of pGSK3b and pFKHR was also significantly decreased in the celecoxib treated-AGS cells. Procaspase 9 (47 kDa) was frequently cleaved into 37, 35 and 17 kDa fragments in the celecoxib-treatment group. However, these changes in cell signal transduction were not observed in the indomethacin treated-AGS cells. Conclusion: The anti-cancer effects of celecoxib on gastric cancer cells might be partly mediated by downregulation of Akt, GSK3b, FKHR, and upregulation of caspase-9, in the mitochondrial apoptotic pathway.

Celecoxib induces apoptosis by inhibiting the expression of survivin in HeLa cells

The effect of celecoxib, a cyclooxygenase-2 selective inhibitor, on a human cervical cancer cell line, HeLa cells, was examined. We found that celecoxib increased DNA ladder formation and the activity of caspase-3, indicating that celecoxib induced apoptosis in HeLa cells. Celecoxib suppressed the expression of an anti-apoptotic protein, survivin, in both protein and mRNA levels. The overexpression of survivin overrode caspase-3 activation induced by celecoxib. Subsequently, we performed luciferase reporter assay with the reporter vector containing human survivin promoter region and electrophoretic mobility shift assay and found that the −75 to −66 bp region relative to the initiating codon played an important role in celecoxib action to suppress survivin promoter activity. Our findings might provide a new insight into the anti-cancer effects of celecoxib.

The Anti-Cancer Effect of COX-2 Inhibitors on Gastric Cancer Cells

Epidemiologic studies have shown that nonsteroidal anti-inflammatory drugs could reduce the risk of cancer development including gastric cancer. This study was performed to identify the antineoplastic mechanism in gastric cancer cells affected by celecoxib, a selective COX-2 inhibitor. MTT assay, ELISA for prostaglandin E(2) (PGE(2)), cell-cycle analyses, immunofluorescent staining, and flow cytometry were performed after treating human gastric cancer cell lines (AGS and MKN-45) with celecoxib or indomethacin. The viabilities of celecoxib-treated cells decreased in a dose- and time-dependent manner compared with indomethacin. Drop of PGE(2) levels was more prominent in the presence of indomethacin than in that of celecoxib. Celecoxib arrested the cell cycle in the G(0)-G(1) phase, which reduced cell numbers in the S phase. Moreover, celecoxib increased the apoptotic cell proportions, a 4-fold increase over control cells. The anticancer effects of celecoxib on gastric cancer cells appear to be mediated by cell-cycle arrest and apoptosis, and not by COX-2 or PGE(2) suppression alone.