Colon microbiota-based drug metabolism has received little attention thus far in the process of drug development, whereas the role of gut microbiota in clinical safety and efficacy of drugs has become more clear. Many of these studies have been performed using animal studies, but the translational value of these data with respect to drug pharmacokinetics, efficacy, and safety is largely unknown. To investigate human colon microbiota-mediated drug metabolism, we applied a recently developed ex vivo fermentation screening platform, in which human colonic microbiota conditions are simulated. A set of 12 drugs (omeprazole, simvastatin, metronidazole, risperidone, sulfinpyrazone, sulindac, levodopa, dapsone, nizatidine, and acetaminophen) was incubated with human colon microbiota under strictly anaerobic conditions and samples were analyzed using HPLC-UV--HRMS analysis. The human microbiota in the fermentation assay consisted of bacterial genera regularly encountered in human colon and fecal samples and could be reproducibly cultured in independent experiments over time. In addition, fully anaerobic culture conditions could be maintained for 24 hours of incubation. Five out of the twelve included drugs showed microbiota-based biotransformation after 24 hours of incubation in the ex vivo fermentation assay, which were sulfasalazine, sulfinpyrazone, sulindac, nizatidine, and risperidone. We demonstrated that drug metabolites formed by microbial metabolism can be detected in a qualitative manner and that the data are in accordance with earlier reported in vivo metabolism. In conclusion, we here present a research tool to investigate human colon microbiota-based drug metabolism that may be applied to enable translatability of microbiota-based drug metabolism.

Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and fourth most frequent reason of cancer-related death throughout the world. About 70% of malignant tumors are related to lifestyle and environmental factors, and better knowledge of their significance might reduce the prevalence of CRC. The cyclooxygenase-2 (COX-2) inhibitory and other direct and indirect pathways of aspirin are translated to inhibition proliferation and enhanced apoptosis of cancer cells. Many studies showed the benefits of aspirin in reducing the risk of CRC development, cancer-related mortality and adenoma prevalence rate in general population, but not in high risk populations. The role of sulindac in CRC prevention is uncertain and the use of this drug is rather uncommon. Celecoxib - COX-2 selective inhibitor- showed efficacy in decreasing of colon adenoma recurrence only in some studies. The protective role of microelements is controversial. The beneficial effects of supplementation of selenium, calcium, folic acid, methionine, antioxidant supplements and probiotics are still not certain. A high energy diet consisting of red meat, animal fat, highly processed foods and unsaturated fats increases the risk of CRC. Carcinogenic role of fat and cholesterol depends on increased production of primary bile acids. The importance of milk and dairy products in CRC prevention is controversial. Fruits, vegetables and grain are considered to have protective effects against adenoma and CRC. Excessive alcohol consumption, smoking, physical inactivity are considered as important CRC risk factors. This article briefly summarizes current state of knowledge about the role of pharmacological and dietary prevention of colorectal cancer. Moreover, it indicates that despite many studies some aspects of this issue are not clear and require future studies.

Metal-ligand coordination involving hydrogen bond functionalized ligands was employed rationally to get an easy access to a series of metallogelators derived from 3-pyridyl derivatives of non-steroidal-anti-inflammatory drugs (NSAIDs) [e.g. ibuprofen, sulindac and flurbiprofen designated as 3-pyIBU, 3-pySUL and 3-pyFLR, respectively] and biogenic metal centers [Zn(II), Cu(II), Mn(II) and Ag(I)]. Thirteen metallogels (MG1-MG13) were obtained by allowing the ligands and the metal salts to react in DMSO/water at room temperature. Slightly different solvent system (DMSO/water/MeOH) afforded four crystalline coordination complexes of 3-pyIBU namely [{Cu(3-pyIBU)4(DMSO)2}(NO3)2] (CC1), [{Ag(3-pyIBU)2}(BF4)] (CC2), [{Ag(3-pyIBU)2}(ClO4)] (CC3) and [{Cu(3-pyIBU)4(CH3OH)2}(OTf)] (CC4) that were fully characterized by single crystal X-ray diffraction (SXRD). However, none of these coordination complexes produced metallogels - the results corroborated well with the rationale based on which the metallogelators were obtained. Two selected metallogels (MG3 and MG9) could be leached out from the corresponding metallogels to the bulk solvent to the extent of 51 and 59 %, respectively after 24 h of incubation at 37 0 C indicating their plausible use in topical application. Moreover, one of the selected metallogelators i.e. MG9 displayed anti-inflammatory response and was able to inhibit the migration of highly aggressive human breast cancer cells MDA-MB-231 suggesting its plausible use as anti-cancer agent.

Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, naproxen, sulindac, celecoxib, and licofelone), statins and other natural agents-both individually, and in combinations. Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.

The nuclear receptor RXRα (retinoid X receptor-α) is a transcription factor that regulates the expression of multiple genes. Its non-genomic function is largely related to its structure, polymeric forms and modification. Previous research revealed that some non-genomic activity of RXRα occurs via formation of heterodimers with Nur77. RXRα-Nur77 heterodimers translocate from the nucleus to the mitochondria in response to certain apoptotic stimuli and this activity correlates with cell apoptosis. More recent studies revealed a significant role for truncated RXRα (tRXRα), which interacts with the p85α subunit of the PI3K/AKT signaling pathway, leading to enhanced activation of AKT and promoting cell growth in vitro and in animals. We recently reported on a series of NSAID sulindac analogs that can bind to tRXRα through a unique binding mechanism. We also identified one analog, K-80003, which can inhibit cancer cell growth by inducing tRXRα to form a tetramer, thus disrupting p85α-tRXRα interaction. This review analyzes the non-genomic effects of RXRα in normal and tumor cells, and discusses the functional differences based on RXRα protein structure (structure source: the RCSB Protein Data Bank).

Sulindac loaded poly(HEMA) cross-linked microparticles were synthesized via one-pot free-radical dispersion polymerisation in supercritical carbon dioxide (scCO2) in presence of photocleavable diblock stabilisers based on polyethylene oxide (PEO) and poly(heptadecafluorodecyl acrylate) (PFDA) bearing a o-nitrobenzyl photosensitive junction (hv) (PEO-hv-PFDA), and ethylene glycol dimethacrylate (EGDMA) as cross-linker. Poly(HEMA) cross-linked microparticles either empty or sulindac loaded were obtained with well-defined spherical morphology with the sizes between 250 and 350 nm. Additionally, upon UV-photolysis the stabiliser on the surface was cleaved which permits to microparticles to be redispersed in water leading to water swollen microgels about 2.1-3.6 µm. Moreover, the release behaviour from obtained microgels indicated the sustained release of sulindac over 10 days. Besides, the surface modification after UV-photolysis was studied and proved that the particles can be functionalised with further chemistries.

Because no information is available on the use of sulindac during breastfeeding, its relatively long half-life and glucuronide metabolite, other agents may be preferred, especially while nursing a newborn or preterm infant.

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 β-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.

The present study aimed to observe the effects of sulindac sulfide on the proliferation and apoptosis of human breast cancer cells MCF-7, and to explore the potential underlying molecular mechanism. The inhibitory ratio was detected using a cell counting kit-8 assay. The changes in cell cycle distribution were assessed using flow cytometry (FCM). Furthermore, the changes in cell apoptosis rates were detected by Hoechst 33258 staining and FCM coupled with Annexin V-FITC/propidium iodide (PI) staining. In addition, the protein expression was detected using western blotting. Sulindac sulfide was able to inhibit the proliferation of breast cancer in a dose- and time-dependent manner. In addition, sulindac sulfide altered the cell cycle of breast cancer cells. The results of Hoechst 33258 staining and FCM coupled with Annexin V-FITC/PI staining demonstrated that sulindac sulfide could significantly induce the apoptosis of MCF-7 cells in a dose-dependent, and time-dependent manner. The western blot analysis demonstrated the protein expression of Bcl-2 was downregulated, and Bax and cleaved caspase-3 were upregulated. The results of the present study suggest that sulindac sulfide can inhibit the proliferation and induce the apoptosis of MCF-7 cells.