Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo

BACKGROUND: 2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex(®)) that lacks COX-2-inhibitory function. However, despite its inability to block COX-2 activity, DMC is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that both of these drugs are able to involve targets other than COX-2 to exert their recognized cytotoxic effects. However, the molecular components that are involved in mediating these drugs' apoptosis-stimulatory consequences are incompletely understood. RESULTS: We present evidence that celecoxib and DMC are able to down-regulate the expression of survivin, an anti-apoptotic protein that is highly expressed in tumor cells and known to confer resistance of such cells to anti-cancer treatments. Suppression of survivin is specific to these two drugs, as other coxibs (valdecoxib, rofecoxib) or traditional NSAIDs (flurbiprofen, indomethacin, sulindac) do not affect survivin expression at similar concentrations. The extent of survivin down-regulation by celecoxib and DMC in different tumor cell lines is somewhat variable, but closely correlates with the degree of drug-induced growth inhibition and apoptosis. When combined with irinotecan, a widely used anticancer drug, celecoxib and DMC greatly enhance the cytotoxic effects of this drug, in keeping with a model that suppression of survivin may be beneficial to sensitize cancer cells to chemotherapy. Remarkably, these effects are not restricted to in vitro conditions, but also take place in tumors from drug-treated animals, where both drugs similarly repress survivin, induce apoptosis, and inhibit tumor growth in vivo. CONCLUSION: In consideration of survivin's recognized role as a custodian of tumor cell survival, our results suggest that celecoxib and DMC might exert their cytotoxic anti-tumor effects at least in part via the down-regulation of survivin – in a manner that does not require the inhibition of cyclooxygenase-2. Because inhibition of COX-2 appears to be negligible, it might be worthwhile to further evaluate DMC's potential as a non-coxib alternative to celecoxib for anti-cancer purposes

Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study.

OBJECTIVES: Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California. METHODS: Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival. RESULTS: The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites. CONCLUSIONS: Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation

COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro

Abstract Background An increasing number of reports is challenging the notion that the antitumor potential of the selective COX-2 inhibitor celecoxib (Celebrex®) is mediated primarily via the inhibition of COX-2. We have investigated this issue by applying two different analogs of celecoxib that differentially display COX-2-inhibitory activity: the first analog, called unmethylated celecoxib (UMC), inhibits COX-2 slightly more potently than its parental compound, whereas the second analog, 2,5-dimethyl-celecoxib (DMC), has lost the ability to inhibit COX-2. Results With the use of glioblastoma and pancreatic carcinoma cell lines, we comparatively analyzed the effects of celecoxib, UMC, and DMC in various short-term (≤48 hours) cellular and molecular studies, as well as in long-term (≤3 months) focus formation assays. We found that DMC exhibited the most potent antitumor activity; celecoxib was somewhat less effective, and UMC clearly displayed the overall weakest antitumor potential in all aspects. The differential growth-inhibitory and apoptosis-stimulatory potency of these compounds in short-term assays did not at all correlate with their capacity to inhibit COX-2, but was closely aligned with their ability to trigger endoplasmic reticulum stress (ERS), as indicated by the induction of the ERS marker CHOP/GADD153 and activation of the ERS-associated caspase 7. In addition, we found that these compounds were able to restore contact inhibition and block focus formation during long-term, chronic drug exposure of tumor cells, and this was achieved at sub-toxic concentrations in the absence of ERS or inhibition of COX-2. Conclusion The antitumor activity of celecoxib in vitro did not involve the inhibition of COX-2. Rather, the drug's ability to trigger ERS, a known effector of cell death, might provide an alternative explanation for its acute cytotoxicity. In addition, the newly discovered ability of this drug to restore contact inhibition and block focus formation during chronic drug exposure, which involved neither ERS nor COX-2, suggests a novel, as yet unrecognized mechanism of celecoxib action.</p

Application of ASCO Value Framework to Treatment Advances in Hepatocellular Carcinoma.

BackgroundDetermination of the comparative efficacy of one therapy over another for hepatocellular carcinoma (HCC) can be challenging. Application of a recognized value framework to published studies could objectively compare the potential benefit across available therapies.Materials and methodsAn umbrella review of phase III trials for HCC therapies was performed. ASCO Value Framework Net Health Benefit Score version 2 (ASCO-NHB v2) scores, the primary analysis, and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 scores, the secondary analysis, were computed using selected drug registration trials. Both scores were compared between drugs that were Food and Drug Administration (FDA)-approved by 2020 and those that were not.ResultsOf the 22 studies identified, nine were FDA-approved and 13 were not. Across 22 trials, the median overall survival (OS) was 9.2 months (range, 1.9-16.4 months), with a median gain of 0.35 month (range, 2.3-3.3 months). HCC therapies that were FDA-approved showed longer OS (median 10.7 v 7.9 months, P &lt; .01) and higher ASCO NHB scores (+18.4 v -5.7 scores, P &lt; .01). The median gain in OS was 2.2 months in the approved treatments compared with -0.3 months in the unapproved group, with no difference in progression-free survival between the two groups.ConclusionThe nine FDA-approved therapies for HCC have higher mean NHB score than those that were not FDA-approved. The application of ASCO-NHB v2 and other proposed value frameworks could examine data of future therapies for HCC through a patient-oriented approach

COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro-4

Ions of CXB, UMC, or DMC. After 48 hours, MTT assays were performed to indicate the overall viability in response drug treatment. The right panels show representative 96-well plates of treated cells. Deep purple indicates fully viable cell cultures, whereas yellow color reveals drug cytotoxicity (each condition was tested in duplicate). The single well labeled "Bg." represents background of medium alone without cells. The charts on the left present the quantitative readout of the optical density of the 96-well plates (average of two wells each). The whole experiment was independently repeated and yielded very similar outcomes.<p><b>Copyright information:</b></p><p>Taken from "COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro"</p><p>Molecular Cancer 2008;7():38-38.</p><p>Published online 16 May 2008</p><p>PMCID:PMC2396175.</p><p></p

COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro-1

48 hours, MTT assays were performed to indicate the overall viability in response drug treatment. The right panels show representative 96-well plates of treated cells. Deep purple indicates fully viable cell cultures, whereas yellow color reveals drug cytotoxicity (each condition was tested in duplicate). The charts on the left present the quantitative readout of the optical density of the 96-well plates (average of two wells each). The whole experiment was independently repeated and yielded very similar outcomes.<p><b>Copyright information:</b></p><p>Taken from "COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro"</p><p>Molecular Cancer 2008;7():38-38.</p><p>Published online 16 May 2008</p><p>PMCID:PMC2396175.</p><p></p

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Ntrations of CXB, DMC, or UMC for up to 2 months in the same cell culture dishes (i.e., without splitting the cell monolayers). In A., cells were treated with or without 20 μM DMC and photomicrographs (400× magnification) were taken after 6 weeks. Note that in the presence of drug (lower panels) the individual cells are noticeably larger, and the overall monolayer consists of fewer cells per surface area. In B., cells were treated with increasing concentrations of CXB and the total number of cells per well (6-well plate) was determined after 4 weeks (shown is the average of two counts). In all instances, the phenotypic changes were similar in the case of CXB, UMC, or DMC (not shown for all treatment conditions), except that DMC was the most potent, and UMC the least potent, compound. These experiments were repeated with very similar outcomes.<p><b>Copyright information:</b></p><p>Taken from "COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro"</p><p>Molecular Cancer 2008;7():38-38.</p><p>Published online 16 May 2008</p><p>PMCID:PMC2396175.</p><p></p

COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro-0

groups (at the 2- and 5-positions). The listed COX-2 inhibitory potency (IC50) of these compounds is derived from two earlier studies that used human recombinant COX-2 in vitro [23, 42]. The bottom chart displays PGElevels (mean ± SE, n = 4) in the culture medium of Bx-PC-3 cells pretreated for 30 minutes with the indicated drug concentrations and then stimulated with 10 μM arachidonic acid, as previously described by Eibl et al. [25].<p><b>Copyright information:</b></p><p>Taken from "COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro"</p><p>Molecular Cancer 2008;7():38-38.</p><p>Published online 16 May 2008</p><p>PMCID:PMC2396175.</p><p></p