sulindac-sulfide and Disease-Models--Animal

Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs.. We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models. We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and. Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies.

Topics: Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Humans; Mice; Sulindac; Triple Negative Breast Neoplasms

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

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 β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/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 β-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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis Regulatory Proteins; beta Catenin; Central Nervous System Neoplasms; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation, Neoplastic; Hemangioma, Cavernous, Central Nervous System; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sulindac; Transforming Growth Factor beta

The subtle modification of a selection of Abeta42 inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), through synthesis of the geminal dimethyl analogues, was anticipated to ablate their cyclooxygenase activity whilst maintaining Abeta42 inhibition. Methylflurbiprofen 6 exhibited similar in vitro Abeta42 inhibition to its parent NSAID Flurbiprofen and was further evaluated in the Tg2576 mouse model of Alzheimer's disease and an animal model of gastro-intestinal (GI) impairment, but proved unviable for further clinical development.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Cyclooxygenase Inhibitors; Disease Models, Animal; Flurbiprofen; Mice; Peptide Fragments

Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide (the 42-residue isoform of the amyloid-beta peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant beta-amyloid precursor protein (APP) lowered their brain levels of Abeta42. In cultured cells, the decrease in Abeta42 secretion was accompanied by an increase in the Abeta(1-38) isoform, indicating that NSAIDs subtly alter gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Abeta42 peptide levels independently of COX activity and that this Abeta42-lowering activity could be optimized to selectively target the pathogenic Abeta42 species.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid Endopeptidases; Brain; CHO Cells; Cricetinae; Disease Models, Animal; Endopeptidases; Enzyme-Linked Immunosorbent Assay; Humans; Ibuprofen; Indomethacin; Mass Spectrometry; Mice; Mice, Transgenic; Peptide Fragments; Prostaglandin-Endoperoxide Synthases; Sulindac; Tumor Cells, Cultured

There is continued debate over any renal sparing effects of sulindac (S): such a property would be of benefit and be unique among nonsteroidal anti-inflammatory drugs (NSAIDS). S undergoes a distinct metabolism whereby the active drug (sulindac sulfide (SS)) does not appear in the urine. Accordingly, we tested the effect of a plasma concentration of SS in the therapeutic range on renal blood flow (RBF), glomerular filtration rate (GFR), and renal prostaglandin (PG) concentrations during sudden renal ischemic stress. The ischemic stress was produced by a 15 to 20% reduction in arterial pressure by arterial hemorrhage (H) in four separate groups of anesthetized dogs: control, SS (0.4 mg/kg i.v. bolus followed by 0.03 mg/kg/min constant infusion), indomethacin (I, 10 mg/kg), and benoxaprofen (B, 75 mg/kg). A plasma concentration of 3.69 micrograms/ml of SS was achieved by the infusion, and no SS appeared in the urine. H reduced GFR (by 46%) and RBF (by 38%) in control dogs; in SS-treated dogs, a 60% decline in GFR and a 73% decrease in RGF occurred. These decreases in renal hemodynamics in the SS group during H were significantly greater than in the control group. Further, these decrements in GFR and RBF were similar to those observed in the I- and B-treated dogs. Finally, SS reduced baseline arterial and renal PG concentrations, and prevented any increase in renal PG release during H. Thus, we conclude that a concentration of SS in the therapeutic range, which does not appear in the urine, is capable of enhancing the decline in GFR and RBF during a sudden ischemic stress such as H.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dogs; Glomerular Filtration Rate; Hemodynamics; Hemorrhage; Indenes; Indomethacin; Ischemia; Kidney; Kidney Diseases; Propionates; Renal Circulation; Sulindac