Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

Effect of Solubility Improvement via Formation of an Amorphous Composite of Indomethacin and Sulindac on Membrane Permeability.

The importance of permeability as well as solubility of the drug has been recognized in improving the solubility of poorly water-soluble drugs. This study investigated the impact of amorphous composites of indomethacin (IMC) and sulindac (SLD) on the membrane permeability of drugs. The IMC/SLD (1/1) formulation prepared by dry grinding was amorphous with a single glass transition temperature. The Fourier transform IR spectra and Raman spectra revealed formation of hydrogen bonds between the OH group of IMC and the carbonyl group of SLD. These results suggest that an amorphous composite was formed between IMC and SLD through hydrogen bonding. The amount of dissolved IMC and SLD from the amorphous composite of IMC/SLD (1/1) was higher than that of the untreated IMC or SLD in the dissolution test. The permeated amounts and permeation rates of both drugs were enhanced by increasing the solubility of the amorphous composite. Conversely, the apparent membrane permeability coefficients (Papp) were almost same for untreated drugs and amorphous composites. In the case of hydroxypropyl-ß-cyclodextrin and sodium dodecyl sulfate, Papp of the drugs decreased with the addition of these compounds, although the drug solubility was enhanced by the solubilization effect. This study revealed that an amorphous composite formed through hydrogen bonding is an attractive pharmaceutical way to enhance the permeated amount and permeation rate without changing the Papp of both the drugs.

Sulindac Improves Stiffness and Quality of Life in Women Taking Aromatase Inhibitors for Breast Cancer.

PURPOSE: To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs). METHODS: Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy-General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models. RESULTS: Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [- 5.85 (- 9.73, - 1.96)] and WOMAC pain [- 5.40 (- 10.64, - 0 .18)], Stiffness [- 9.53 (- 14.98, - 4.08)] and Physical Function [- 5.61 (- 9.62, - 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity. CONCLUSIONS: Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT01761877, December, 2012.

Usefulness of Optimized Human Fecal Material in Simulating the Bacterial Degradation of Sulindac and Sulfinpyrazone in the Lower Intestine.

The first aim of this study was to evaluate the usefulness of optimized human fecal material in simulating sulforeductase activity in the lower intestine by assessing bacterial degradation of sulindac and sulfinpyrazone, two sulforeductase substrates. The second aim was to evaluate the usefulness of drug degradation half-life generated in simulated colonic bacteria (SCoB) in informing PBPK models. Degradation experiments of sulfinpyrazone and of sulindac in SCoB were performed under anaerobic conditions using recently described methods. For sulfinpyrazone, the abundance of clinical data allowed for construction of a physiologically based pharmacokinetic (PBPK) model and evaluation of luminal degradation clearance determined from SCoB data. For sulindac, the availability of sulindac sulfide and sulindac sulfone standards allowed for evaluating the formation of the main metabolite, sulindac sulfide, during the experiments in SCoB. Both model compounds degraded substantially in SCoB. The PBPK model was able to adequately capture exposure of sulfinpyrazone and its sulfide metabolite in healthy subjects, in ileostomy and/or colectomy subjects, and in healthy subjects pretreated with metoclopramide by implementing degradation half-lives in SCoB to calculate intrinsic colon clearance. Degradation rates of sulindac and formation rates of sulindac sulfide in SCoB were almost identical, in line with in vivo data suggesting the sulindac sulfide is the primary metabolite in the lower intestine. Experiments in SCoB were useful in simulating sulforeductase related bacterial degradation activity in the lower intestine. Degradation half-life calculated from experiments in SCoB is proven useful for informing a predictive PBPK model for sulfinpyrazone.

Photoisomerization of Sulindac and Ozagrel Hydrochloride by Vitamin B2 Catalyst Under Visible Light Irradiation.

PURPOSE: Photoisomerization of the E/Z-alkene structures of drugs is a matter of concern as it could result in potency loss and adverse side effects. This study focused on light-induced isomerization of sulindac and ozagrel hydrochloride catalyzed by concomitant vitamin B2 under light-emitting diode (LED) or fluorescent light. METHODS: In the presence of 0.05/0.03 equivalents of vitamin B2/flavin adenine dinucleotide (FAD), sulindac or ozagrel hydrochloride was irradiated with LED light (405 nm) or fluorescent light. The photoisomerization in CD3OD and D2O was monitored by 1H NMR spectroscopy. RESULTS: Sulindac and ozagrel hydrochloride isomerized in the presence of a catalytic amount of vitamin B2 or FAD under irradiation of 405 nm LED light and fluorescent light. Irradiation with LED light was found to be more effective than fluorescent light irradiation. The rate of photoisomerization was affected by the solvent, and the reaction in CD3OD proceeded faster than in D2O. Furthermore, ozagrel hydrochloride was more prone to isomerization than sulindac. CONCLUSION: The catalytic activity of vitamin B2 or FAD was demonstrated in the photoisomerization reaction of sulindac and ozagrel hydrochloride. Considering that the rate of photoisomerization in D2O is very slow, the possibility of the occurrence of photoisomerization during clinical use is low. However, this study suggests that the interfusion of vitamin B2 or FAD under excessive light exposure should be avoided as a caution during intravenous administration of sulindac or ozagrel hydrochloride.

Sulindac and vitamin D3 synergically inhibit proliferation of MCF-7 breast cancer cell through AMPK/Akt/ß-catenin axis in vitro.

Breast cancer is associated with a high rate of recurrence, resistance therapy and mortality worldwide. We aimed at investigating the inhibitory effects of Sulindac and vitamin D3 (VD) on MCF-7 human breast cancer cells. MCF-7 cells were cultured with different concentrations of Sulindac and VD over a period of 24, 48 and 72 hours for cell viability and IC50 experiments. Hochst staining was used to evaluate apoptosis, whereas quantitative PCR (qPCR) was performed to measure mRNA levels of BCL-2 and BAX genes. Immunofluorescence staining was used to monitor intracellular ß-catenin expression. The protein levels of AKT, AMPK and P65 were measured by western blotting. The result showed that cell viability decreased in treated cells dose/time dependently (P < .05). Hochst staining showed an increase in fragmented nuclei in treated cells. The expression of BCL-2 and BAX genes decreased and increased in treated cells, respectively (P < .05). Immunofluorescence staining indicated that the expression of ß-catenin significantly reduced in treated cells. The AKT-1/p-Akt-1 and AMPK/p-AMPK ratio increased in treated cells (P < .05), but the P65/p-P65 ratio did not change significantly (P > .05). Our results indicated that the combination of Sulindac and VD has a growth-inhibiting effect on MCF-7 cells through AMPK/Akt/ß-catenin axis.

Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid. METHODS: As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apcmin/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries. RESULTS: Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone. CONCLUSIONS: Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.

The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations.

OBJECTIVE: To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. METHODS: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. RESULTS: Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. CONCLUSIONS: The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Population Pharmacokinetics of Sulindac and Genetic Polymorphisms of FMO3 and AOX1 in Women with Preterm Labor.

PURPOSE: This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor. METHODS: Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. CONCLUSIONS: Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.

Novel sulindac derivatives: synthesis, characterisation, evaluation of antioxidant, analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibition activity.

A new series of N'-(substituted phenyl)-2-(1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide derivatives (1 - 25) were prepared in good yields in an efficient manner. All the compounds were fully characterised by the elemental analysis and spectral data. Synthesised compounds were evaluated for antioxidant activity by DPPH method. Compounds 7 (R = 3-methoxyphenyl), 3 (R = 4-dimethylaminophenyl) and 23 (R = 2,4,5-trimethoxy phenyl) substitutions were found to be having highly potent antioxidant activity. Compound 3, with para dimethylaminophenyl substitution was found to be having highest antioxidant activity. It was further evaluated in vivo for various analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibitory activity in different animal models. Lead compound 3 was found to be significant anti-inflammatory and analgesic agent. It was also evaluated for ulcerogenic activity and demonstrated significant ulcerogenic reduction activity in ethanol and indomethacin model. The LD50 of compound 3 was found to be 131 mg/kg. The animals treated with compound 3 prior to cisplatin treatment resulted in a significant reduction in COX-2 protein expression when compared to cisplatin-treated group. Sulindac derivative with para dimethylaminophenyl substitution was found to be the most potent antioxidant, anti-inflammatory and analgesic agent as well as with significant gastric sparing activity as compared to standard drug sulindac. Compound 3 significantly downregulated liver tissue COX-2 gene expression.

Identification of the Effects of Aspirin and Sulindac Sulfide on the Inhibition of HMGA2-Mediated Oncogenic Capacities in Colorectal Cancer.

Distant metastatic colorectal cancer (CRC) is present in approximately 25% of patients at initial diagnosis, and eventually half of CRC patients will develop metastatic disease. The 5-year survival rate for patients with metastatic CRC is a mere 12.5%; thus, there is an urgent need to investigate the molecular mechanisms of cancer progression in CRC. High expression of human high-mobility group A2 (HMGA2) is related to tumor progression, a poor prognosis, and a poor response to therapy for CRC. Therefore, HMGA2 is an attractive target for cancer therapy. In this study, we identified aspirin and sulindac sulfide as novel potential inhibitors of HMGA2 using a genome-wide mRNA signature-based approach. In addition, aspirin and sulindac sulfide induced cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration. Moreover, a gene set enrichment analysis (GSEA) revealed that gene sets related to inflammation were positively correlated with HMGA2 and that the main molecular function of these genes was categorized as a G-protein-coupled receptor (GPCR) activity event. Collectively, this is the first study to report that aspirin and sulindac sulfide are novel potential inhibitors of HMGA2, which can induce cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration through influencing inflammatory-response genes, the majority of which are involved in GPCR signaling.

Preparation and Characterization of PVA-Co-PE Drug-Loaded Nanofiber Membrane by Electrospinning Technology.

A new transdermal drug delivery system of nanofiber membrane with good biocompatibility and high drug loading was developed by electrospinning technology in this study. Using vinyl alcohol-co-ethylene (PVA-co-PE) polymer as a spinning matrix and non-steroidal anti-inflammatory drug (NSAID) sulindac (SUL) as a model drug, the SUL@PVA-co-PE nanofiber membrane was prepared and characterized systematically. The morphology, molecular vibrational transitions, thermogravimetric attributes, and in vitro drug release and transdermal characteristics of drug-loaded nanofiber membranes were analyzed. The results indicated that the surface of PVA-co-PE nanofibers was uniform and smooth with the diameter ranged from 461 to 696 nm. Notably in vitro simulation experiments demonstrated that SUL@PVA-co-PE nanofiber membrane could provide a continuous drug release to reach the effective concentration of the drug, and exhibited significantly higher cumulative drug permeability compared to commercially available patches, Taken together, PVA-co-PE nanofiber membranes exhibited the characteristics of high drug loading and stability, and represented the potential to be utilized as a new transdermal drug delivery carrier with pronounced development prospect.

Treatment of cancer stem cells from human colon adenocarcinoma cell line HT-29 with resveratrol and sulindac induced mesenchymal-endothelial transition rate.

In the current experiment, the combined regime of resveratrol and a Wnt-3a inhibitor, sulindac, were examined on the angiogenic potential of cancer stem cells from human colon adenocarcinoma cell line HT-29 during 7 days. Cancer stem cells were enriched via a magnetic-activated cell sorter technique and cultured in endothelial induction medium containing sulindac and resveratrol. Expression of endothelial markers such as the von Willebrand factor (vWF) and vascular endothelial cadherin (VE-cadherin) and genes participating in mesenchymal-to-epithelial transition was studied by real-time PCR assay. Protein levels of Wnt-3a and angiogenic factor YKL-40 were examined by western blotting. ELISA was used to determine the level of N-acetylgalactosaminyltransferase 11 (GALNT11) during mesenchymal-endothelial transition. Autophagy status was monitored by PCR array under treatment with the resveratrol plus sulindac. Results showed that resveratrol and sulindac had the potential to decrease the cell survival of HT-29 cancer cells and the clonogenic capacity of cancer stem cells compared with the control (p < 0.05). The expression of VE-cadherin and vWF was induced in cancer stem cells incubated with endothelial differentiation medium enriched with resveratrol (p < 0.05). Interestingly, the Wnt-3a level was increased in the presence of resveratrol and sulindac (p < 0.05). YKL-40 was reduced after cell exposure to sulindac and resveratrol. The intracellular content of resistance factor GALNT11 was diminished after treatment with resveratrol (p < 0.05). Resveratrol had the potential to induce the transcription of autophagy signaling genes in cancer stem cells during endothelial differentiation (p < 0.05). These data show that resveratrol could increase cancer stem cell trans-differentiation toward endothelial lineage while decrease cell resistance by modulation of autophagy signaling and GALNT11 synthesis.

Pharmacological targeting of RAS: Recent success with direct inhibitors.

RAS has long been viewed as undruggable due to its lack of deep pockets for binding of small molecule inhibitors. However, recent successes in the development of direct RAS inhibitors suggest that the goal of pharmacological inhibition of RAS in patients may soon be realized. This review will discuss the role of RAS in cancer, the approaches used to develop direct RAS inhibitors, and highlight recent successes in the development of novel RAS inhibitory compounds that target different aspects of RAS biochemistry. In particular, this review will discuss the different properties of RAS that have been targeted by various inhibitors including membrane localization, the different activation states of RAS, effector binding, and nucleotide exchange. In addition, this review will highlight the recent success with mutation-specific inhibitors that exploit the unique biochemistry of the RAS(G12C) mutant. Although this mutation in KRAS accounts for 11% of all KRAS mutations in cancer, it is the most prominent KRAS mutant in lung cancer suggesting that G12C-specific inhibitors may provide a new approach for treating the subset of lung cancer patients harboring this mutant allele. Finally, this review will discuss the involvement of dimerization in RAS function and highlight new approaches to inhibit RAS by specifically interfering with RAS:RAS interaction.

Optimizing the timing of colorectal surgery in patients with familial adenomatous polyposis in clinical practice.

Background: Familial adenomatous polyposis (FAP) is characterized by the development of hundreds of colorectal adenomas in the second decade of life, and prophylactic colectomy is usually performed around age of 20. A common question is the appropriate timing of surgery and which endoscopic findings indicate surgery. Methods: All FAP patients known at Leiden University Medical Centre from 1985 onwards were included. The patients were then subdivided into those diagnosed before or after 2000. Patient information included age at diagnosis, colonic phenotype, age at surgery, pathological findings and the outcome of follow-up colonoscopies in whom surgery was postponed. Results: The 72 FAP patients identified consisted of 33 patients diagnosed before (group A) and 39 after (group B) 2000. The median age at diagnosis for patients with classical FAP was 18 in groups A and B. All patients diagnosed before 2000 underwent colorectal surgery versus 68% of those diagnosed >2000. The median age at surgery for classical FAP patients was 19 and 24 years in groups A and B, respectively. In patients with intact colon, the number of adenomas gradually increased over many years. Although most adenomas remained <5 mm, the proportion of 5-15 mm adenomas slowly increased. Only one patient developed a high-grade adenoma. None of the patients developed CRC. Conclusions: Surgery today in FAP is performed less often and at a more advanced age. Our experience also suggests that surgery can be safely postponed in selected patients. The most important endoscopic indication for surgery is substantial number of large adenomas of >5-10 mm.

Nonselective Cyclooxygenase Inhibition Retards Cyst Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease.

Aim: Autosomal dominant polycystic kidney disease is one of the most common genetic renal diseases. Cyclooxygenase plays an important role in epithelial cell proliferation and may contribute to the mechanisms underlying cyst formation. The aim of the present study was to evaluate the role of cyclooxygenase inhibition in the cyst progression in polycystic kidney disease. Method: Pkd2WS25/- mice, a murine model which harbors a compound cis-heterozygous mutation of the Pkd2 gene were used. Cyclooxygenase expression was assessed in both human and murine kidney specimens. Pkd2WS25/- mice were treated with Sulindac (a nonselective cyclooxygenase inhibitor) or vehicle for 8 months starting at three weeks age, and then renal cyst burden was assessed by kidney weight and volume. Results: Cyclooxygenase-2 expression was up-regulated compared to control kidneys as shown by RNase protection in human polycystic kidneys and immunoblot in mouse Pkd2WS25/- kidneys. Cyclooxygenase-2 expression was up-regulated in the renal interstitium as well as focal areas of the cystic epithelium (p<0.05). Basal Cyclooxygenase-1 levels were unchanged in both immunohistochemistry and real-time PCR. Administration of Sulindac to Pkd2WS25/- mice and to control mice for 8 months resulted in reduced kidney weights and volume in cystic mice. Renal function and electrolytes were not significantly different between groups. Conclusion: Thus treatment of a murine model of polycystic kidney disease with Sulindac results in decreased kidney cyst burden. These findings provide additional implications for the use of Cyclooxygenase inhibition as treatment to slow the progression of cyst burden in patients with polycystic kidney disease.

Sulindac sulfone inhibits the mTORC1 pathway in colon cancer cells by directly targeting voltage-dependent anion channel 1 and 2.

Sulindac sulfone is a metabolite of sulindac, a non-steroidal anti-inflammatory drug (NSAID), without anti-inflammatory ability. However, sulindac sulfone has been reported to significantly reduce polyps in patients with colorectal adenomatous polyposis in clinical trials. Thus, sulindac sulfone is expected to be useful for the chemoprevention of neoplasia with few side effects related to anti-inflammatory ability. To date, the molecular targets of sulindac sulfone have not yet fully investigated. Therefore, in order to newly identify sulindac sulfone-binding proteins, we generated sulindac sulfone-fixed FG beads and purified sulindac sulfone-binding proteins from human colon cancer HT-29 cells. we identified mitochondrial outer membrane proteins voltage-dependent anion channel (VDAC) 1 and VDAC2 as novel molecular targets of sulindac sulfone, and sulindac sulfone directly bound to both VDAC1 and VDAC2. Double knockdown of VDAC1 and VDAC2 by siRNA inhibited growth and arrested the cell cycle at G1 phase in HT-29 cells. Depletion of VDAC1 and VDAC2 also inhibited the mTORC1 pathway with a reduction in cyclin D1. Interestingly, these effects were consistent with those of sulindac sulfone against human colon cancer cells, suggesting that sulindac sulfone negatively regulates the function of VDAC1 and VDAC2. In the present study, our data suggested that VDAC1 and VDAC2 are direct targets of sulindac sulfone which suppresses the mTORC1 pathway and induces G1 arrest.

A small diversity library of α-methyl amide analogs of sulindac for probing anticancer structure-activity relationships.

Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer's disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.

Chemopreventive effect of sulindac in combination with epigallocatechin gallate or kaempferol against 1,2-dimethyl hydrazine-induced preneoplastic lesions in rats: A Comparative Study.

A systematic investigation of the chemopreventive effect of sulindac (SL) in combination with either epigallocatechin gallate (EGCG) or kaempferol similar (KMP) has been carried out 1,2-dimethyl hydrazine-treated rats (DMH). Those SL combinations with KMP and EGCG have enhanced the SL activity producing greater antioxidant, anti-inflammatory, antiproliferating, and apoptotic activities in both combinations than SL alone. The chemopreventive effects of SL with both EGCG and KMP were demonstrated by a decrease in thiobaribituric acid reactive substances level, tissue nitric oxide (NO), serum, and tissue ß-catenin as well as a reduction in the multiplicity of aberrant crypt foci (ACF) with alleviation in the dysplastic changes that resulted from DMH administration. Down-regulation of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) were also confirmed by immunohistochemical staining. The current study paves the way for the use of sulindac combination with kaempferol or EGCG as potential chemopreventive agents against colon cancer with more effect in combination with EGCG.

Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice.

Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of ß-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a ß-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-ß/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate ß-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.