Overexpression Of Cyclooxygenase-2 Research Articles

739. SIGNIFICANCE OF COX2 INHIBITOR FOR ESOPHAGEAL CANCER FROM THE CLINICAL AND EXPERIMENTAL ESTIMATE

Abstract (Aims) We report experimental and clinical evidence that COX2 represent a potential molecular target for the treatment and prevention of esophageal cancer. (Methods) (A)Experiment: Thirty 8-week male wistar rats were exposed to duodenal content esophageal reflux. All animal underwent an esophagoduodenal anastomosis (EDA) with total gastrectomy in order to produce chronic esophagitis. In ten rats the sham (Control). They were sacrified at 40th week. Their esophagi were examined for HE, COX2,PGE2, PCNA and total bile acids in the esophageal lumen was measured. (B)Clinical: The expression of COX2 was examined for 68 specimens of esophageal squamous cell carcinoma (SCC) and the correlation of COX2 expression with clinicopatholigic features was examined. (Results) (A) After 40 weeks of reflux, columnar dysplasia, squamous cell carcinoma and adenocarcinoma were found. Total bile acid in the esophageal lumen was significantly increased in the EDA group compared with the sham operated rats. PCNA LI and esophageal tissue PGE2 were higher in dysplastic and cancer tissue than that of control. Overexpression of COX2 was shown in dysplastic and cancer tissue. COX2 may play an important role in esophageal cancer by duodenal content reflux.(B) COX2 immunoreactivity was weak in 27(40%) and strong in 41(60%) of the carcinomas. The proportion of poorly differentiated SCC among tumors with a strong expression of COX2 (34%) was significantly higher than among tumors with a weak expression of COX2 (19%, p=0.02). The depth of tumors (p=0.004), lymph node metastasis (p=0.0009) and the stage of the tumors (p=0.001) were advanced significantly more progressively in ECCS with a strong COX2 expression. Moreover, survival was significantly reduced (p=0.02) among patients with strong COX2 expression when compared with the COX2 weak group. This study showed that strong expression of COX2 was correlated with tumor progression and poor differentiation in ESCC. (Conclusion) In this experimental study, we demonstrate that bile reflux of duodenal contents induce COX2 and increase prostaglandin synthesis in dysplastic and cancer tissue. Our study suggests that COX2 may play a role in esophageal carcinoma development and progression, COX2 inhibitors may be potential targets for the prevention or treatment of esophageal carcinoma.

741. EXPRESSION OF COX2 AND P53 IN RAT ESOPHAGEAL CANCER INDUCED BY REFLUX OF DUODENAL CONTENTS

Abstract Aim. Reflux of duodenal contents can induce mucosal injury, stimulate cell proliferation, and promote tumorigenesis. We examined the expression of COX2 and p53 in rat esophageal lesions induced by duodenal content reflux. Methods. Thirty 8-week-old male Wistar rats were exposed to duodenal content esophageal reflux. All animals underwent an esophagoduodenal anastomosis (EDA) with total gastrectomy in order to produce chronic esophagitis. Ten rats were the sham. Control. They were sacrificed at the 40th week. Their esophagi were examined for HE, COX2, p53, and proliferating cell nuclear antigen (PCNA). Results. After 40 weeks of reflux, dysplasia, squamous cell carcinoma (SCC), and adenocarcinoma (ADC) were found. PCNA labeling index was higher in dysplastic and cancer tissue than that in normal. Overexpression of COX2 was shown in ADC and SCC. Wild-type p53 accumulation was found in ADC, and not in SCC. Conclusion. Reflux of duodenal contents into the esophagus led to ADC and SCC in rats. COX2 may play an important role in esophageal cancer by duodenal content reflux. Our present results suggest an association between wild-type p53 accumulation and COX2 expression in ADC, with no such relation seen in SCC.

Systematic establishment of the relationship between skin absorption and toxicity of furanoids via in silico, in vitro, and in vivo assessments

Furanoids are a class of contaminants prevalent in both airborne and occupational environments, with potential health implications through inhalation, oral ingestion, and skin penetration. Given their diminutive molecular size, there is a presumption that furanoids can readily permeate the skin. To systematically explore this presumption, we investigated the skin absorption and toxicity of a series of furans (furfuryl alcohol, furfuryl acetate, furfural, methyl 2-furoate, and 5-methylfurfural) using in silico, in vitro, and in vivo models. The in vitro permeation test (IVPT) from neat and aqueous suspension (5 mM) of furans demonstrated a facile absorption through pig and nude mouse skins. The lipophilicity of furans significantly influenced skin deposition, with higher lipophilicity displaying greater deposition. However, an opposing trend emerged in the receptor compartment accumulation. In barrier-defective skin simulating atopic dermatitis (AD) and psoriasis, enhanced deposition occurred with more hydrophilic furans but not with the more lipophilic ones. In the cell-based study, furanoids induced the proliferation of keratinocytes and skin fibroblasts except for the compounds with the aldehyde group (furfural and 5-methylfurfural). Both furfuryl acetate and 5-methylfurfural activated keratinocytes via the overexpression of COX-2 and PGE2 by 1.5‒2-fold. This stimulation involved the mitogen-activated protein kinase (MAPK) signaling pathway. For the in vivo mouse skin treatment, we selected furfuryl acetate (hydrophilic) and 5-methylfurfural (lipophilic). Both furans showed different patterns of skin lesions, where repeated application of furfuryl acetate caused epidermal hyperplasia and scaling, while 5-methylfurfural predominantly evoked skin inflammation and barrier disintegration. Toxicokinetics analysis revealed a higher plasma concentration of topically applied furfuryl acetate than that of the 5-methylfurfural (5.04 versus 2.34 nmol/ml), resulting in the mild injury of furfuryl acetate-treated peripheral organs. Conversely, no notable adverse effects on organs were observed for the 5-methylfurfural. This study established the relationship between cutaneous absorption and the toxicity of furans following skin exposure.

Lonicera japonica Thunb. Ethanol Extract Exerts a Protective Effect on Normal Human Gastric Epithelial Cells by Modulating the Activity of Tumor-Necrosis-Factor-α-Induced Inflammatory Cyclooxygenase 2/Prostaglandin E2 and Matrix Metalloproteinase 9.

Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy

Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting “cold” tumors into “hot” tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.

To study the utility of COX-2 as immunohistochemical prognostic marker in comparison to various histopathological parameters and TNM staging in breast carcinoma: an observational, cross-sectional study protocol.

Breast cancer is the most prevalent cancer among women worldwide and is a well-known cause for cancer mortality in females. COX-2 (cyclooxygenase) plays a vital role in development of some human cancers such as lung, colon and breast. It is a potent enzyme that is important for the conversion of arachidonic acid into prostaglandins. These prostaglandins mediate cellular proliferation, apoptosis and angiogenesis which contributes to carcinogenesis. Overexpression of COX-2 has been detected in several malignancies including breast cancer. COX-2 overexpression is regarded as a poor prognostic marker of breast cancer.The present study will aim to study the immunohistochemical expression of COX-2 in breast cancer and compare it with known histopathological parameters thus assessing its prognostic value. This will be an observational study conducted in the Department of Pathology, JNMC, Wardha (Sawangi). Radical mastectomy specimens will be studied for COX-2 expression by immunohistochemistry in patients diagnosed with breast carcinoma. COX-2 expression will be quantified as immunohistochemical score and results will be correlated with various histopathological parameters. The expected result of our study will suggest an association of COX-2 expression to the factors associated with poor prognosis in breast carcinoma. A positive correlation is expected between larger tumor size, positive lymph node status, higher T stage and N stage and lymphovascular invasion. Conclusions will be drawn from the obtained results of the immunohistochemical study by using COX-2- for detection of overexpression of COX-2 when evaluated with TNM staging, histological grading and molecular types of breast cancer.

A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.

Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.

Immunohistochemical Expression Levels of Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Ki-67 in Canine Cutaneous Squamous Cell Carcinomas

Squamous cell carcinoma (SCC) stands as the second most prevalent skin cancer in dogs, primarily attributed to UV radiation exposure. Affected areas typically include regions with sparse hair and pale or depigmented skin. The significance of spontaneous canine cutaneous SCC as a model for its human counterpart is underscored by its resemblance. This study assesses the expression of key markers—Epidermal Growth Factor Receptor (EGFR), Cyclooxygenase-2 (Cox-2), and Ki-67—in canine cutaneous SCC. Our objective is to investigate the association between their expression levels and classical clinicopathological parameters, unraveling the intricate relationships among these molecular markers. In our retrospective analysis of 37 cases, EGFR overexpression manifested in 43.2% of cases, while Cox-2 exhibited overexpression in 97.3%. The EGFR, Cox-2 overexpression, and Ki-67 proliferation indices, estimated through immunohistochemistry, displayed a significant association with the histological grade, but only EGFR labeling is associated with the presence of lymphovascular emboli. The Ki-67 labeling index expression exhibited an association with EGFR and Cox-2. These findings propose that EGFR, Cox-2, and Ki-67 hold promise as valuable markers in canine SCC. EGFR, Cox-2, and Ki-67 may serve as indicators of disease progression, offering insights into the malignancy of a lesion. The implications extend to the potential therapeutic targeting of EGFR and Cox-2 in managing canine SCC. Further exploration of these insights is warranted due to their translational relevance and the development of targeted interventions in the context of canine SCC.

Contribution of non-steroidal anti-inflammatory drugs to breast cancer treatment: In vitro and in vivo studies.

Chronic inflammation plays a crucial role in carcinogenesis. High levels of serum prostaglandin E2 and tissue overexpression of cyclooxygenase-2 (COX-2) have been described in breast, urinary, colorectal, prostate, and lung cancers as being involved in tumor initiation, promotion, progression, angiogenesis, and immunosuppression. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for several medical conditions to not only decrease pain and fever but also reduce inflammation by inhibiting COX and its product synthesis. To date, significant efforts have been made to better understand and clarify the interplay between cancer development, inflammation, and NSAIDs with a view toward addressing their potential for cancer management. This review provides readers with an overview of the potential use of NSAIDs and selective COX-2 inhibitors for breast cancer treatment, highlighting pre-clinical in vitro and in vivo studies employed to evaluate the efficacy of NSAIDs and their use in combination with other antineoplastic drugs.

A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging.

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.

Synthesis and in vitro characterization of naproxen derivatives as novel anti-inflammatory agents

Naproxen, one type of non-steroidal anti-inflammatory drugs, has excellent anti-inflammatory activity. However, long-term use of it causes serious adverse effects. Inspired by the biological diversification of cinnamic acid, novel naproxen derivatives containing cinnamic acid are synthesized and used to improve their anti-inflammatory activity and safety. Our results indicated that thirty naproxen derivatives have different inhibitory effects on RAW264.7 macrophage cells. It is showed that most of the target naproxen derivatives possess the lower degree of cytotoxicity than that of naproxen. Further studies indicated that compound 22 (IC50 = 8.74 ± 2.13 μM) concentration-dependently inhibits the over-expression of iNOS, COX-2 and IL-1β by blocking the activation of nuclear factor kappa-B (NF-κB) signaling pathway and NLRP-3 inflammasome, respectively. Docking studies showed that the binding of compound 22 to NLRP3 using a well-fitting mode. It is found that compound 22 will be a novel anti-inflammatory agent to treat inflammatory diseases with an improved safety profile.

Hypersampsonone H attenuates ulcerative colitis via inhibition of PDE4 and regulation of cAMP/PKA/CREB signaling pathway

Background and objectivesUlcerative colitis (UC) is a recurrent intestinal inflammatory disease which poses a serious threat to the life of patients. However, there are no specific drugs for UC yet. Hypericum sampsonii Hance (HS) is a Chinese herbal medicine traditionally used to treat enteritis and dysentery. Our previous studies have demonstrated that HS holds potential anti-UC effects, and a novel compound named Hypersampsonone H (HS-1) isolated from HS possesses significant anti-inflammatory activity. However, the beneficial effects of HS-1 on UC remain unclear. This study aimed to investigate the therapeutic effects of HS-1 on UC and its potential mechanisms, both in vitro and in vivo. MethodsThe in vitro model was employed using LPS-induced RAW264.7 cells to investigate the anti-inflammatory effects of HS-1 and its possible mechanisms. Furthermore, the therapeutic efficacy and potential mechanisms of HS-1 against dextran sulfate sodium (DSS)-induced acute colitis were assessed through histopathological examination, biochemical analysis, and molecular docking. ResultsIn vitro, HS-1 significantly reduced LPS-induced inflammatory responses, as indicated by inhibiting NO production, down-regulating the overexpression of COX-2 and iNOS, as well as regulating the imbalanced levels of IL-6, TNF-α, and IL-10. Moreover, HS-1 also inhibited the expression of PDE4, elevated the intracellular cAMP level, and promoted the phosphorylation of CREB, thereby activating the PKA/CREB pathway in RAW264.7 cells. In vivo, HS-1 demonstrated therapeutic capacity against DSS-induced colitis by alleviating the symptoms of colitis mice, regulating the abnormal expression of inflammatory mediators, protecting the integrity of intestinal epithelial barrier, and reducing tissue fibrosis. Consistently, HS-1 was found to decrease the expression of PDE4 isoforms, subsequently activating the cAMP/PKA/CREB signaling pathway. Furthermore, the molecular docking results indicated that HS-1 exhibited a high affinity for PDE4, particularly PDE4D. Further mechanistic validation in vitro demonstrated that HS-1 possessed a synergistic effect on forskolin and an antagonistic effect on H-89 dihydrochloride, thereby exerting anti-inflammatory effects through the cAMP/PKA/CREB signaling pathway. ConclusionWe disclose that HS-1 serves as a promising candidate drug for the treatment of UC by virtue of its ability to reduce DSS-induced colitis via the inhibition of PDE4 and the activation of cAMP/PKA/CREB signaling pathway.

Investigating Cox-2 and EGFR as Biomarkers in Canine Oral Squamous Cell Carcinoma: Implications for Diagnosis and Therapy.

Oral squamous cell carcinoma (OSCC) is a common and highly aggressive dog tumor known for its local invasiveness and metastatic potential. Understanding the molecular mechanisms driving the development and progression of OSCC is crucial for improving diagnostic and therapeutic strategies. Additionally, spontaneous oral squamous cell carcinomas in dogs are an excellent model for studying human counterparts. In this study, we aimed to investigate the significance of two key molecular components, Cox-2 and EGFR, in canine OSCC. We examined 34 tumor sections from various dog breeds to assess the immunoexpression of Cox-2 and EGFR. Our findings revealed that Cox-2 was highly expressed in 70.6% of cases, while EGFR overexpression was observed in 44.1%. Cox-2 overexpression showed association with histological grade of malignancy (HGM) (p = 0.006) and EGFR with vascular invasion (p = 0.006). COX-2 and EGFR concurrent expression was associated with HGM (p = 0.002), as well as with the presence of vascular invasion (p = 0.002). These data suggest that Cox-2 and EGFR could be promising biomarkers and potential therapeutic targets, opening avenues for developing novel treatment strategies for dogs affected by OSCC. Further studies are warranted to delve deeper into these findings and translate them into clinical practice.

Immunohistochemical Expression and Prognostic Value of COX-2 and Alpha-Smooth Muscle Actin-positive Cancer-associated Fibroblasts in Feline Mammary Cancer.

Cyclo-oxygenase-2 (COX-2) and cancer associated fibroblasts (CAFs) play an important role in the development and progression of tumor malignancy in humans and animals, showing that both can influence the tumor microenvironment. However, the impact of these two markers in feline mammary carcinogenesis has not yet been addressed. In the present study, the clinicopathological significance of COX-2 immunoexpression and alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) was determined and correlated with disease-free and overall survival of 50 felines with malignant mammary tumors. COX-2 overexpression was positively associated with mitotic index (p=0.031), degree of malignancy (p≤0.001), lymph node metastasis (p≤0.001), vascular invasion (p=0.002), disease recurrence (p=0.019) and distant metastasis (p=0.036). α-SMA-positive CAFs were associated with mitotic index (p=0.004), lymph node metastasis (p=0.027), vascular invasion (p=0.05), disease recurrence (p≤0.001) and distant metastasis (p≤0.001). Additionally, both markers were correlated with disease-free and overall survival, emerging as predictors of poor prognosis. Our results indicate for the first time that the presence of two markers, COX-2 and α-SMA, is associated with carcinogenesis and worse prognosis in feline mammary cancer and that α-SMA-positive CAFs have a role in feline mammary tumorigenesis, cancer development, and clinical outcome.

Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116.

Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(iv) conjugates derived from Pt(ii) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, 2 was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of 2 is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that 2 inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.

Cyclooxygenase-2 Blockade Is Crucial to Restore Natural Killer Cell Activity before Anti-CTLA-4 Therapy against High-Grade Serous Ovarian Cancer.

Chronic inflammation influences the tumor immune microenvironment (TIME) in high-grade serous ovarian cancer (HGSOC). Specifically, cyclooxygenase-2 (COX-2) overexpression promotes cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression. Notably, elevated COX-2 levels in the TIME have been associated with reduced response to anti-CTLA-4 immunotherapy. However, the precise impact of COX-2, encoded by PTGS2, on the immune profile remains unknown. To address this, we performed an integrated bioinformatics analysis using data from the HGSOC cohorts (TCGA-OV, n = 368; Australian cohort AOCS, n = 80; GSE26193, n = 62; and GSE30161, n = 45). Employing Gene Set Variation Analysis (GSVA), MIXTURE and Ecotyper cell deconvolution algorithms, we concluded that COX-2 was linked to immune cell ecosystems associated with shorter survival, cell dysfunction and lower NK cell effector cytotoxicity capacity. Next, we validated these results by characterizing circulating NK cells from HGSOC patients through flow cytometry and cytotoxic assays while undergoing COX-2 and CTLA-4 blockade. The blockade of COX-2 improved the cytotoxic capacity of NK cells against HGSOC cell lines. Our findings underscore the relevance of COX-2 in shaping the TIME and suggest its potential as a prognostic indicator and therapeutic target. Increased COX-2 expression may hamper the effectivity of immunotherapies that require NK cell effector function. These results provide a foundation for experimental validation and clinical trials investigating combined therapies targeting COX-2 and CTLA-4 in HGSOC.

Exploring the CXCR4/CXCR7/CXCL12 Axis in Primary Desmoid Tumors.

Desmoid tumors have an extremely variable natural history. The uncertainty behind desmoid behavior reflects the complexity, which subtends its development and non-linear advancement. Apart from Wnt- βcatenin mutation, estrogen receptors, and COX-2 overexpression, little is known about the ability of desmoids to grow and recur while being unable to metastasize. Several tumors have been shown to express the CXCR4/CXCR7/CXCL12 axis, whose functions are essential for tumoral development. This study aimed to investigate the expression of the CXCR4/CXCR7/CXCL12 axis in primary desmoid tumors and discuss the potential role of this key-signaling as an antiangiogenic therapeutic strategy. In this study, 3 μm-thick consecutive sections from each formalin-fixed and paraffin-embedded tissue block were treated with mouse monoclonal antibodies developed against CD34, CXCR4, CXCR7, and CXCL12. Two distinct vessel populations: CXCR4+ and CXCR4- vessels, have been found. Similarly, chemokine receptor CXCR7 expression in the entire desmoid tumor series positively stained a portion of tumor-associated vessels, identifying two distinct subpopulations of vessels: CXCR7+ and CXCR7- vessels. All 8 neoplastic tissue samples expressed CXCL12. Immunohistochemical positivity was identified in both stromal and endothelial vascular cells. Compared to CXCR4 and CXCR7, the vast majority of tumor-associated vessels were found to express this chemokine. It is the first time, as per our knowledge, that CXCR4/CXCR7/CXCL12 axis expression has been identified in a desmoid type-fibromatosis series. CXCL12 expression by neoplastic cells, together with CXCR4 and CXCR7 expression by a subgroup of tumor-associated vessels, was detected in all desmoid tumor tissue samples examined. Since chemokines are known contributors to neovascularization, CXCR4/CXCR7/CXCL12 axis may play a role in angiogenesis in this soft-tissue tumor histotype, thereby supporting its growth.

A combination of all-trans retinoic acid derivative and COX-2 inhibitor has anticancer effects in human pharyngeal carcinoma cells

Backgrounds and aimsCarcinogenesis is characterized by an unlimited growth of cells exacerbated by Cox-2 overexpression. Cox-2 inhibitors have been proven effective in preventing and treating tumors. In our previous studies, we found that 4-Amino-2-Trifluoromethylphenyl Retinate (ATPR) induces cell apoptosis and inhibits cell proliferation to exhibit anti-cancer properties. The use of ATRA as well as Cox-2 inhibitors in clinical settings can cause adverse reactions. It is unknown what the effects and mechanisms of co-administration of ATPR and Cox-2 inhibitors are. ResultsA combination of ATPR and Cox-2 inhibitors, Celecoxib, inhibited pharyngeal cancer cell proliferation in vitro and induced apoptosis. The cell cycle was arrested at G0/G1 by activating P53 and CDNA1. By activating MAPK/JNK pathways, ATPR and Celecoxib led to intrinsic and extrinsic apoptosis in pharyngeal cancer cells. ATPR/Celecoxib combined treatment suppressed tumor growth in the pharyngeal cancer cell-derived xenograft mouse model by increasing the number of apoptotic cells. The expression of the RARA and PTGS2 genes was significantly increased in tumor tissue compared to non-tumor tissue in the clinical analysis of the head and neck squamous cell carcinoma dataset. An association was found between this and the level of intrinsic apoptotic signals. Furthermore, a survival analysis conducted over a period of five years indicated that higher levels of RARA expression were associated with a better clinical outcome. ConclusionATPR and celecoxib inhibit the proliferation of cancer cells as well as induce apoptosis. Co-administration of ATPR and Cox-2 inhibitors has the potential to be a novel treatment plan for cancer.

Prospects of new targeted nanotherapy combining liponiosomes with berberine to combat colorectal cancer development: An in vivo experimental model

Colorectal cancer (CRC) is one of the most identified and deadly malignancies worldwide. It presents a serious challenge due to its quick growth, which finally culminates in severe malignancy. It is critical to improve the efficacy of berberine (BR) as an anticancer agent to overcome its limited bioavailability. Implementation of a novel, effective nanocarrier system of liponiosomes for BR (LipoNio.BR) can support mechanistic actions associated with its anti-CRC role. Following CRC induction in rats using 1,2 Dimethylhydrazine (40 mg DMH/kg/week), the potency and mechanistic actions of LipoNio.BR were assessed by evaluating the lesion severity and molecular mechanisms controlling oxidative stress, apoptosis, autophagy, and inflammatory responses, and conducting histopathological and immunohistochemistry examinations of colonic tissues. The results indicated that the severity of clinical signs comprising weight gain loss, increased diarrhea and rectal bleeding, and reduced survivability were greatly restored in the LipoNio.BR-treated group. LipoNio.BR remarkably reduced CRC development compared to FBR (free berberine), as it induced apoptosis via upregulating apoptotic genes (Bax and caspase3, increased up to 7.89 and 6.25-fold, respectively) and downregulating the anti-apoptotic gene Bcl-2 by 2.25-fold. LipoNio.BR mitigated the oxidative stress associated with CRC and maintained redox homeostasis. Notably, the excessive inflammatory response associated with CRC was prominently reduced following administration of LipoNio.BR [which decreased iterleukin (IL-B, IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), proliferating cell nuclear antigen (PCNA), follistatin, and activin BA (beta-A) expression]. LipoNio.BR modulated the expression of nuclear factor kappa B (NF-κB) and mammalian target of rapamycin (mTOR), which impacted tumor vascularity (decreased Vascular endothelial growth factor (VEGF) expression by 2.36-fold). The severity of the histopathological alterations in the colonic tissues, including the development of neoplastic epithelium and the invasion of some neoplastic masses, was greatly reduced in the LipoNio.BR group compared to the FBR-(free berberine) administrated group. Following CRC induction, immunohistochemical staining revealed that the overexpression of cyclin and COX-2 in colonic tissues were suppressed in the LipoNio.BR group. Taken together, these findings suggest that LipoNio.BR has a potential role in reducing CRC progression to a greater extent compared to free BR and could be considered a promising and potent therapy against CRC.

Evaluation of cyclooxygenase-2, P53, vascular endothelial growth factor, and nitric oxide synthase-2 in angiogenesis and growth of tobacco-related malignancies

Objectives: In India, tobacco consumption is responsible for half of all the cancers in men and a quarter in women. The present study focuses on the expression of cyclooxygenase-2 (COX-2), P53, vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS) and their relationship with the growth and angiogenesis of tobacco-related malignancies of the oral cavity, esophagus, lungs, and stomach. It further evaluates the carcinogenic action of nicotine and examines whether COX-2 and NOS-2 overexpression is responsible for tumor growth and associated angiogenic VEGF expression via its receptor. Materials and Methods: A cross-sectional study on 140 biopsies, resected specimens of cancer of oral cavity, esophagus, stomach, and lungs, was done. Immunohistochemical evaluation for p53, COX-2, VEGF, and inducible NOS was done. Relevant statistical analysis was applied for the significance of the findings. Statistical Analysis: Relevant statistical analysis was done using SPSS, chi-square and Fisher's exact tests were applied for the significance of the findings. A p-value of < 0.05 was considered as significant value. Results: Immunohistochemical evaluation of pattern of expression of COX-2, NOS-2, VEGF, and p53 was done in both tobacco- and nontobacco-associated cases. The results of the present study revealed an upregulation of COX-2, NOS-2, VEGF, and p53 in all the malignancies. Conclusion: The present results indicated that p53 protein accumulation and increased expression of COX-2, NOS-2, and VEGF might be responsible for carcinogenesis and tumor aggressiveness by enhancing angiogenesis. A possible significant effect of nicotine on COX-2 and P53 expression in tumorigenesis is revealed. These data might have important implications for the therapeutic use of COX-2, NOS-2, and VEGF inhibitors as well as of p53 gene therapy in future anticancer therapeutic strategies in tobacco-related malignancies.