Celecoxib reduces fluidity and decreases metastatic potential of colon cancer cell lines irrespective of COX-2 expression

Sade, Asli; Tunçay, Seda; Çimen, İsmail; Severcan, Feride; Banerjee, Sreeparna

doi:10.1042/bsr20100149

Cited by 34 publications

(31 citation statements)

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“…We found that celecoxib and DMC cause inhibition with an IC 50 of 40 μM and 36 μM, respectively. These findings correlate well with experimental and clinical studies where dimethyl celecoxib works as well as celecoxib, which points to a COX-2-independent mode of action (48–59). The measured IC50’s of celecoxib and DMC are comparable to known celecoxib plasma concentrations in patients.…”

Section: Experimental Validationsupporting

confidence: 89%

Predicting New Indications for Approved Drugs Using a Proteochemometric Method

et al. 2012

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The most effective way to move from target identification to the clinic is to identify already approved drugs with the potential for activating or inhibiting unintended targets (repurposing or repositioning). This is usually achieved by high throughput chemical screening, transcriptome matching, or simple in silico ligand docking. We now describe a novel rapid computational proteochemometric method called "train, match, fit, streamline" (TMFS) to map new drug−target interaction space and predict new uses. The TMFS method combines shape, topology, and chemical signatures, including docking score and functional contact points of the ligand, to predict potential drug−target interactions with remarkable accuracy. Using the TMFS method, we performed extensive molecular fit computations on 3671 FDA approved drugs across 2335 human protein crystal structures. The TMFS method predicts drug−target associations with 91% accuracy for the majority of drugs. Over 58% of the known best ligands for each target were correctly predicted as top ranked, followed by 66%, 76%, 84%, and 91% for agents ranked in the top 10, 20, 30, and 40, respectively, out of all 3671 drugs. Drugs ranked in the top 1−40 that have not been experimentally validated for a particular target now become candidates for repositioning. Furthermore, we used the TMFS method to discover that mebendazole, an antiparasitic with recently discovered and unexpected anticancer properties, has the structural potential to inhibit VEGFR2. We confirmed experimentally that mebendazole inhibits VEGFR2 kinase activity and angiogenesis at doses comparable with its known effects on hookworm. TMFS also predicted, and was confirmed with surface plasmon resonance, that dimethyl celecoxib and the anti-inflammatory agent celecoxib can bind cadherin-11, an adhesion molecule important in rheumatoid arthritis and poor prognosis malignancies for which no targeted therapies exist. We anticipate that expanding our TMFS method to the >27 000 clinically active agents available worldwide across all targets will be most useful in the repositioning of existing drugs for new therapeutic targets.

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Section: Experimental Validationsupporting

confidence: 89%

Predicting New Indications for Approved Drugs Using a Proteochemometric Method

et al. 2012

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“…However, accumulating evidence indicates that COX-2 inhibition is not the only basis for the anticancer effects of aspirin; other targets have been identified, and researchers have begun to recognize that this old drug has a startling variety of effects (Alfonso et al, 2014). We herein show that aspirin induces cellular senescence in SW620 and HCT116 cells, which are known to lack COX-2 expression (Liu et al, 2003;Sade et al, 2012). We further tested whether aspirin or celecoxib, two known COX-1/2 inhibitors (Seedher and Bhatia, 2003), could induce senescence in COX-2-expressing HT-29 cells.…”

Section: Discussionmentioning

confidence: 90%

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

et al. 2015

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Cancer therapies attempt to destroy the entire tumor, but this tends to require toxic compounds and high doses of radiation. Recently, considerable attention has focused on therapyinduced senescence (TIS), which can be induced in cancer cells by low doses of therapeutic drugs or radiation and provides a barrier to tumor development. However, the molecular mechanisms governing TIS remain elusive. Special attention has been paid to the potential chemopreventive effect of aspirin against human colorectal cancer. In this study, we investigated the effects of aspirin on TIS of human colorectal carcinoma (CRC) cells and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. Small-interfering RNA-mediated downregulation or pharmacological inhibition of SIRT1 or AMPK significantly attenuated the aspirininduced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog induced cellular senescence. Remarkably, SIRT1 knockdown abrogated the aspirin-induced activation of AMPK, and vice versa. During the progression of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at a relatively early time point but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Collectively, these novel findings suggest that aspirin could provide anticancer effects by inducing senescence in human CRC cells through the reciprocal regulation of SIRT1-AMPK pathways.

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“…19 Additionally, using ATR-FTIR and Electron Spin Resonance (ESR) Spectroscopy, we have previously shown that treatment of colon cancer cells with Celecoxib resulted in decreased membrane fluidity, which was correlated with a decrease in motility of these cells. 20 We have shown here that treatment of colon cancer cell lines HT29 and SW620 with VLX could effectively reverse the detrimental effects of chronic inflammation in cells, along with a decrease in lipid fluidity, an increase in the unsaturation level and an increase in the acyl length and chain order. These properties may contribute towards the therapeutic efficacy of VLX on colon cancer.…”

Section: Discussionmentioning

confidence: 94%

Valdecoxib Recovers the Lipid Composition, Order and Dynamics in Colon Cancer Cell Lines Independent of COX-2 Expression: An ATR-FTIR Spectroscopy Study

et al. 2016

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Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenases (COXs). Aberrant expression of the inducible isoform COX-2 plays a significant role in colon cancer initiation and progression. In this study, we have hypothesized that COX-2 specific inhibitors such as Valdecoxib (VLX), being highly hydrophobic, may alter biophysical properties of cellular lipids. In this study, COX-2 expressing (HT29) and COX-2 non-expressing (SW620) colon cancer cell lines were treated with VLX and examined using attenuated total reflection infrared spectroscopy. The results revealed that VLX treatment decreased lipid fluidity in the cells irrespective of COX-2 expression status and affected order parameters of the lipids in both cell lines. Cluster analysis also indicated that the spectral differences between the two cell lines are profound and could be successfully differentiated. Valdecoxib treatment could enhance the composition, order and dynamics of the lipids of colon cancer cells independently of its COX-2 inhibitory mechanism. Valdecoxib has therapeutic effects upon colon cancer, therefore it can be used as an adjuvant and/or chemopreventive agent for colon cancer.

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Celecoxib reduces fluidity and decreases metastatic potential of colon cancer cell lines irrespective of COX-2 expression

Cited by 34 publications

References 50 publications

Predicting New Indications for Approved Drugs Using a Proteochemometric Method

Predicting New Indications for Approved Drugs Using a Proteochemometric Method

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

Valdecoxib Recovers the Lipid Composition, Order and Dynamics in Colon Cancer Cell Lines Independent of COX-2 Expression: An ATR-FTIR Spectroscopy Study

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