Celecoxib

Celecoxib is a highly selective inhibitor of cyclooxygenase-2 (COX-2) with IC50 value of 40nM [1].

In vitro, celecoxib not only reduced the production of PGE2 but also inhibited the downstream effects of PGE2. Celecoxib blocked migration and invasion of A549 cells increased by PGE2 in the wound healing and transwell assays.  Additionally, celecoxib reduced MMP9 mRNA expression which was increased by PGE2. Moreover, celecoxib enhanced E-cadherin mRNA expression which was inhibited by PGE2 [2].

In vivo, celecoxib inhibited the increase in metastases of A549 cells and significantly reduced the increase in PGE2 plasma level in mice receiving unilateral pneumonectomy [2].

References:
[1] Penning TD1, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS,AndersonGD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). J Med Chem. 1997 Apr 25;40(9):1347-65.
[2] Zhang S1, Da L1, Yang X1, Feng D1, Yin R1, Li M1, Zhang Z1, Jiang F2, Xu L3. Celecoxib potentially inhibits metastasis of lung cancer promoted by surgery in mice, via suppression of the PGE2-modulated β-catenin pathway.

Toxicol Lett. 2014 Mar 3;225(2):201-7.

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naive Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial.[Pubmed:28300506]

J Clin Oncol. 2017 May 10;35(14):1530-1541.

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two Celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for >/= 2 years (nonmetastatic); prostate (+/- pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.

A stratified randomized double-blind phase II trial of celecoxib for treating patients with cervical intraepithelial neoplasia: The potential predictive value of VEGF serum levels: An NRG Oncology/Gynecologic Oncology Group study.[Pubmed:28285845]

Gynecol Oncol. 2017 May;145(2):291-297.

PURPOSE: To examine the effect of Celecoxib on cervical intraepithelial neoplasia 3 (CIN 3). This is a NRG Oncology/Gynecologic Oncology Group study with translational biomarkers. PATIENTS AND METHODS: Patients with CIN 3 were randomized to Celecoxib 400mg once daily (67 patients) or placebo (63 patients) for 14-18weeks. The primary outcome measure was histologic regression. A test of equal probabilities of success between two therapies was conducted, using Fisher's Exact Test at alpha=10% and 90% power when the treatment arm boosted the probability of success by 30%. Translational analysis included cervical tissue HPV genotyping, COX-2 expression in biopsies, and serum Celecoxib and VEGF levels. RESULTS: In primary analysis, histologic regression was not significantly higher in the Celecoxib group (40%) than in the placebo group (34.1%). However, exploratory analyses suggest patients with high serum VEGF levels exhibited greater regression in the Celecoxib arm (47.3%) than in the placebo arm (14.3%). Regression rates were similar by treatment group in patients with low VEGF. VEGF levels increased over time in the placebo group, but remained the same in the treatment group. COX-2 expression in cervical biopsies declined from pre-treatment to the end of treatment with Celecoxib; it did not change with placebo. CONCLUSIONS: Celecoxib at 400mg once daily for 14-18weeks did not significantly decrease the severity of CIN 3 compared with placebo except, possibly, in subjects with high baseline VEGF. Therefore, serum VEGF levels might identify patients who may benefit from Celecoxib or other therapies, personalizing future chemoprevention trials for CIN 3.

Celecoxib-erlotinib combination treatment enhances radiosensitivity in A549 human lung cancer cell.[Pubmed:28282799]

Cancer Biomark. 2017;19(1):45-50.

BACKGROUND: Radiosensitivity by blocking the epidermal growth factor receptor and cyclooxygenase-2 pathways with erlotinib and Celecoxib in A549 human lung cancer cell was investigated. METHODS: MTT assays were used to detect the antitumor effects of erlotinib and Celecoxib in A549 cells. Colony formation assays were used to evaluate the antitumor effects. Flow cytometry analysis was used to assess the cell cycle and cell apoptosis, and western blotting analysis was performed to evaluate the expression of AKT and phosphorylated AKT. RESULTS: Either erlotinib or Celecoxib inhibited the A549 cell proliferation in a dose-dependent manner. Combining Erlotinib or Celecoxib with radiation can suppress the cell colony formation and the Dq, D0, SF2 of the combining erlotinib or Celecoxib with radiation was lower than in the combinations either erlotinib or Celecoxib with radiation (t= 6.62, P< 0.05). The SER of radiation with Celecoxib or erlotinib and Celecoxib and erlotinib were 1.299, 1.503 and 2.217, respectively. The Flow cytometry analysis results showed that either Celecoxib or erlotinib could induce G0/G1 arrest, and reduction of S phase cell proportion, especially when combinations erlotinib-Celecoxib with radiation. Either Celecoxib or erlotinib could enhance radiation-induced apoptosis, especially significant when combinations erlotinib-Celecoxib with radiation. Moreover, radiation can promote the expression of pAKT, and the pAKT was remarkably lowest in the combinations erlotinib-Celecoxib with radiation group (t= 4.89, P< 0.05). CONCLUSIONS: Blocking both EGFR- and COX-2-related pathways could enhance the antitumor effect of radiation. The underlying mechanisms including the enhancement of apoptosis and radiation-induced G0/G1 arrest, possibly via inhibiting the PI3K/AKT signaling pathway.

Isobolographic Analyses of Proglumide-Celecoxib Interaction in Rats with Painful Diabetic Neuropathy.[Pubmed:28370133]

Drug Dev Res. 2017 Mar;78(2):116-123.

Preclinical Research The aim of the present study was to analyze the antihyperalgesic and antiallodynic interaction between the non-selective cholecystokinin (CCK) antagonist receptor, proglumide, and the selective cyclooxygenase-2 inhibitor, Celecoxib in streptozotocin (STZ)-induced diabetic rats. Hyperalgesia was evaluated in the formalin test and tactile allodynia using von Frey filaments. Isobolographic analyses were employed to define the nature of the compound interactions, using a fixed dose ratio (0.5:0.5). Proglumide (20-160 mg/kg) and Celecoxib (0.3-30 mg/kg) in these fixed dose ratio combinations induced dose-dependent antihyperalgesia and an antiallodynic effect in diabetic rats. ED40 values were calculated for the treatments and an isobologram was constructed. Theoretical ED40 values for combination proglumide-Celecoxib estimated from the isobolograms for antihyperalgesic and antiallodynic activity (30.50 +/- 1.90 mg/kg and 45.81 +/- 4.55 mg/kg, respectively) were obtained, while experimental ED40 values for this antihyperalgesic and antiallodynic combined effect (13.83 +/- 0.65 mg/kg and 17.74 +/- 3.57 mg/kg; respectively) were significantly different. Coadministration of proglumide-Celecoxib showed an interaction index value of 0.45 +/- 0.03 for the antihyperalgesic effect and 0.39 +/- 0.08 for the antiallodynic activity, indicating a synergistic interaction. These data suggest that proglumide and Celecoxib can interact synergistically to reduce hyperalgesic and allodynic behaviors in diabetic neuropathy. This combination could be useful to treat neuropathic pain in diabetic patients. Drug Dev Res 78 : 116-123, 2017. (c)2017 Wiley Periodicals, Inc.

Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor.[Pubmed:10786667]

Cancer Res. 2000 Apr 15;60(8):2101-3.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed to reduce the relative risk of breast cancer. This prompted our investigation of the chemopreventive potential of Celecoxib, a specific cyclooxygenase 2 blocker, against mammary carcinogenesis induced by 7,12-dimethyl-benz(a)anthracene in female Sprague Dawley rats. Treatment with Celecoxib was examined and compared to treatment with the general NSAID, ibuprofen, and to a control group receiving only dimethylbenz(a)anthracene. Dietary administration of Celecoxib (1500 ppm) produced striking reductions in the incidence, multiplicity, and volume of breast tumors relative to the control group (68%, 86%, and 81%, respectively; P < 0.001). Ibuprofen also produced significant effects, but of lesser magnitude (40%, 52%, and 57%, respectively; P < 0.001). These results help confirm the chemopreventive activity of NSAIDs against breast cancer and provide the first evidence that a cyclooxygenase 2 blocking agent, Celecoxib, possesses strong chemopreventive activity against mammary carcinogenesis.

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib).[Pubmed:9135032]

J Med Chem. 1997 Apr 25;40(9):1347-65.

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, Celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.