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Cureus Jan 2024Sulindac sulfone, an active metabolite of sulindac, a non-steroidal anti-inflammatory drug, has good anti-inflammatory potential. The antineoplastic effect of sulindac... (Review)
Review
Sulindac sulfone, an active metabolite of sulindac, a non-steroidal anti-inflammatory drug, has good anti-inflammatory potential. The antineoplastic effect of sulindac sulfone is mediated through a cyclooxygenase inhibitory mechanism, followed by apoptosis and inhibition of cell proliferation. Mounting studies have explored the anti-neoplastic effect of sulindac sulfone in various types of cancers in a dose-dependent manner. In this backdrop, we have conducted a systematic review to evaluate the efficacy and dose of sulindac sulfone as an anti-neoplastic agent in human head and neck squamous cell carcinoma cell lines (HNSCCs). In this study, we used a systematic literature review approach, and articles were searched in PubMed, and Medline with the keywords "sulindac sulfone," "anti-neoplastic activity," "chemopreventive," and "head and neck squamous cell carcinoma". A hand-search of journals was also performed. Articles were reviewed and analyzed. The analysis reveals that, based on the in vitro studies on various tumor models, the optimum concentration of sulindac sulfone which elicits anti-neoplastic effects is 200-800 µM. The anti-neoplastic effect is mediated through inhibition of cell proliferation and apoptosis. The results of our systematic review show that the anti-neoplastic activity of pharmacologic Sulindac sulfone is part of its dose-dependent activity, which can be safely employed in the therapy for human HNSCCs and would be responsible for a beneficial outcome of the treatment.
PubMed: 38313951
DOI: 10.7759/cureus.51692 -
Cancer Research Communications Jan 2023The goal of this project was to utilize mechanistic simulation to demonstrate a methodology that could determine drug combination dose schedules and dose intensities...
The goal of this project was to utilize mechanistic simulation to demonstrate a methodology that could determine drug combination dose schedules and dose intensities that would be most effective in eliminating multidrug resistant cancer cells in early-stage colon cancer. An agent-based model of cell dynamics in human colon crypts was calibrated using measurements of human biopsy specimens. Mutant cancer cells were simulated as cells that were resistant to each of two drugs when the drugs were used separately. The drugs, 5-flurouracil and sulindac, have different mechanisms of action. An artificial neural network was used to generate nearly two hundred thousand two-drug dose schedules. A high-performance computer simulated each dose schedule as a clinical trial and evaluated each dose schedule for its efficiency to cure (eliminate) multidrug resistant cancer cells and its toxicity to the host, as indicated by continued crypt function. Among the dose schedules that were generated, 2430 dose schedules were found to cure all multidrug resistant mutants in each of the 50 simulated trials and retained colon crypt function. One dose schedule was optimal; it eliminated multidrug resistant cancer cells with the minimum toxicity and had a time schedule that would be practical for implementation in the clinic. These results demonstrate a procedure to identify which combination drug dose schedules could be most effective in eliminating drug resistant cancer cells. This was accomplished using a calibrated agent-based model of a human tissue, and a high-performance computer simulation of clinical trials.
Topics: Humans; Computer Simulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Colonic Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36685168
DOI: 10.1158/2767-9764.crc-22-0271 -
Carcinogenesis Aug 2021Barrett's esophagus (BE) is the main known precursor condition of esophageal adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous...
Barrett's esophagus (BE) is the main known precursor condition of esophageal adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is probably mediated by chronic esophageal inflammation, secondary to gastroesophageal reflux disease in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high-fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, whereas both NSAIDs were effective chemoprevention agents in the accelerated HFD-fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.
Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemoprevention; Diet, High-Fat; Disease Models, Animal; Esophageal Neoplasms; Mice; Phenotype; Sulindac
PubMed: 33878160
DOI: 10.1093/carcin/bgab032 -
Journal of Therapeutic Ultrasound 2017Desmoid tumors are benign but locally aggressive non-malignant tumors derived from fibroblasts. Surgery, chemotherapy, and radiation therapy have been the mainstay of...
BACKGROUND
Desmoid tumors are benign but locally aggressive non-malignant tumors derived from fibroblasts. Surgery, chemotherapy, and radiation therapy have been the mainstay of treatment, but recurrence is common and side effects can result in significant morbidity. In this case series, we highlight our experiences performing treatments in the thigh, including strategies for optimizing ablation size and safety.
CASE PRESENTATION
Since December 2014, 14 magnetic resonance-guided focused ultrasound (MRgFUS) treatments for desmoid tumors were performed at our institution in seven patients. Nine of these treatments were completed in three patients with large tumors within the posterior thigh. The first was a 7-year-old boy who had previously been treated with surgical resection, intra-operative radiation, along with courses of vinblastine/methotrexate and sorafenib. Pretreatment tumor volume was 770 cm with 75% non-enhancing volume following the initial treatment. The first treatment was complicated by a third-degree far-field skin burn. Enhanced safety measures were developed to protect the far-field skin. The patient had four subsequent treatments over 14 months, without complication, with non-perfused volume of 85% on current imaging. The second patient was a 21-year-old woman who had previously taken sulindac and celecoxib but had no other therapy. Pretreatment tumor volume was 740 cm. The lateral decubitus position was used to minimize the amount of energy through the sciatic nerve. The first treatment resulted in a relatively low non-perfused volume of 30%. A follow-up treatment resulted in 75-80% ablation of the target. The third patient was a 14-year-old girl with no prior treatment. Pretreatment tumor volume was approximately 440 cm. The sciatic nerve was encased by the anteromedial portion of the mass. A lateral decubitus position and enhanced safety measures were again used. The first treatment resulted in a relatively low non-perfused volume of 30%, likely related to low energies. The second treatment resulted in 70-80% ablation.
CONCLUSIONS
MRgFUS is an effective treatment for desmoid tumors of the thigh with a favorable side effect profile, allowing for repeated treatments if necessary. Ablation size and safety can be improved with far-field coupling devices, careful patient positioning, and optimized sonication planning.
PubMed: 28174660
DOI: 10.1186/s40349-017-0081-3 -
Scientific Reports Aug 2014A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac...
A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the -301 to -253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.
Topics: Antineoplastic Agents; Apoptosis; Binding Sites; Cell Line, Tumor; Colonic Neoplasms; DNA Fragmentation; HCT116 Cells; Humans; Kruppel-Like Transcription Factors; Mutagenesis, Site-Directed; Promoter Regions, Genetic; RNA Interference; RNA, Messenger; RNA, Small Interfering; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sulindac; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation
PubMed: 25102912
DOI: 10.1038/srep06000 -
Archives of Biochemistry and Biophysics Jan 2021Human flavin-containing monooxygenase 3 (FMO3) is a membrane-bound, phase I drug metabolizing enzyme. It is highly polymorphic with some of its variants demonstrating...
Human flavin-containing monooxygenase 3 (FMO3) is a membrane-bound, phase I drug metabolizing enzyme. It is highly polymorphic with some of its variants demonstrating differences in rates of turnover of its substrates: xenobiotics including drugs as well as dietary compounds. In order to measure its in vitro activity and compare any differences between the wild type enzyme and its polymorphic variants, we undertook a systematic study using different engineered proteins, heterologously expressed in bacteria, purified and catalytically characterized with 3 different substrates. These included the full-length as well as the more soluble C-terminal truncated versions of the common polymorphic variants (E158K, V257M and E308G) of FMO3 in addition to the full-length and truncated wild-type proteins. In vitro activity assays were performed with benzydamine, tamoxifen and sulindac sulfide, whose products were measured by HPLC. Differences in catalytic properties between the wild-type FMO3 and its common polymorphic variants were similar to those observed with the truncated, more soluble versions of the enzymes. Interestingly, the truncated enzymes were better catalysts than the full-length proteins. The data obtained point to the feasibility of using the more soluble forms of this enzyme for in vitro drug assays as well as future biotechnological applications possibly in high throughput systems such as bioelectrochemical platforms and biosensors.
Topics: Humans; Models, Molecular; Oxidation-Reduction; Oxygen; Oxygenases; Polymorphism, Genetic; Protein Conformation
PubMed: 33152328
DOI: 10.1016/j.abb.2020.108663 -
The Journal of Clinical Investigation Aug 2017Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical...
Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.
Topics: 5-Lipoxygenase-Activating Proteins; Androgens; Animals; Arachidonate 5-Lipoxygenase; Dihydrotestosterone; Female; Humans; Hydroxyurea; Leukocytes; Leukotrienes; Lipoxygenase Inhibitors; Male; Mice; Pyrroles; Rats; Rats, Wistar; Sex Factors; Sulindac; Testosterone
PubMed: 28737505
DOI: 10.1172/JCI92885 -
Bioinformation 2022It is of interest to document the Molecular Dynamics Simulation and docking analysis of NF-κB target with sulindac sodium in combating COVID-19 for further...
It is of interest to document the Molecular Dynamics Simulation and docking analysis of NF-κB target with sulindac sodium in combating COVID-19 for further consideration. Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that is marketed by Merck under the brand name Clinoril. We show the binding features of sulindac sodium with NF-κB that can be useful in drug repurposing in COVID-19 therapy.
PubMed: 36518123
DOI: 10.6026/97320630018170 -
Journal of Thrombosis and Haemostasis :... Jun 2023Hemorrhage, in particular noncompressible hemorrhage, is the leading cause of casualties in combat trauma and civilian trauma. Although systemic agents can stop bleeding...
An anticoagulant/procoagulant self-converting and bleeding site-targeting systemic nanotherapy for rapidly controlling noncompressible bleeding without risk of thrombosis.
BACKGROUND
Hemorrhage, in particular noncompressible hemorrhage, is the leading cause of casualties in combat trauma and civilian trauma. Although systemic agents can stop bleeding at both inaccessible and accessible injury sites, the application of systemic hemostats in clinics is strictly limited by the nontargeting ability of hemostats and their subsequent potential for thromboembolic complications.
OBJECTIVES
To engineer an anticoagulant/procoagulant self-converting and bleeding site-targeting systemic nanohemostat to rapidly control noncompressible bleeding without thrombosis risk.
METHODS
A multiscale computer simulation was taken to guide the self-assembly of sulindac (SUL, a prodrug of the antiplatelets agent) and poly-L-lysine (a cation polymer with platelets activation ability) for forming poly-L-lysine/SUL nanoparticles (PSNs). In vitro platelet-adhering ability, platelet activation effect, and hemostasis activity of PSNs were evaluated. Then, the biosafety, level of thrombosis, targeting ability, and hemostasis effect of systemic applied PSNs were carefully evaluated in various hemorrhage models.
RESULTS
PSNs were successfully prepared and showed good platelet adhesion and activation in vitro. The bleeding site-targeting ability and hemostatic efficiency in different bleeding models were leveled up by PSNs markedly compared with vitamin K and etamsylate in vivo. SUL in PSNs could be metabolized into sulindac sulfide at clot sites in 4 hours for antiplatelet aggregation, thus reducing thrombotic risk compared with other hemostatic agents, via the ingenious utilization of prodrug metabolism in terms of time intervals and the adhesion on platelets.
CONCLUSION
PSNs are expected to be a low-cost, safe, efficient, clinically translatable first-aid hemostat for first-aid scenarios.
Topics: Humans; Anticoagulants; Computer Simulation; Polylysine; Prodrugs; Hemorrhage; Hemostasis; Hemostatics; Thrombosis
PubMed: 36871669
DOI: 10.1016/j.jtha.2023.02.020 -
Cancers Jan 2019Store-operated Ca entry (SOCE) is the most important Ca entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca store content and enhanced SOCE...
Store-operated Ca entry (SOCE) is the most important Ca entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal colonic cells display small, Ca-selective currents driven by Orai1 channels. In contrast, CRC cells display larger, non-selective currents driven by Orai1 and transient receptor potential canonical type 1 channels (TRPC1). Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in polyamine biosynthesis, strongly prevents CRC, particularly when combined with sulindac. We asked whether DFMO may reverse SOC remodeling in CRC. We found that CRC cells overexpress ODC and treatment with DFMO decreases cancer hallmarks including enhanced cell proliferation and apoptosis resistance. Consistently, DFMO enhances Ca store content and decreases SOCE in CRC cells. Moreover, DFMO abolish selectively the TRPC1-dependent component of SOCs characteristic of CRC cells and this effect is reversed by the polyamine putrescine. Combination of DFMO and sulindac inhibit both SOC components and abolish SOCE in CRC cells. Finally, DFMO treatment inhibits expression of TRPC1 and stromal interaction protein 1 (STIM1) in CRC cells. These results suggest that polyamines contribute to Ca channel remodeling in CRC, and DFMO may prevent CRC by reversing channel remodeling.
PubMed: 30642111
DOI: 10.3390/cancers11010083