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Sulindac (MK-231)

Alias: Sulindac; Aflodac;MK231; MK 231; Algocetil; MK-231;
Cat No.:V1042 Purity: ≥98%
Sulindac(Aflodac; Algocetil; MK231; MK 231;MK-231), belonging to the arylalkanoic acid class of non-steroidal antiinflammatory drugs (NSAIDs), isa non-steroidal COX inhibitor, which potently inhibits prostaglandin synthesis.
Sulindac (MK-231)
Sulindac (MK-231) Chemical Structure CAS No.: 38194-50-2
Product category: COX
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Sulindac (MK-231):

  • Sulindac Sulfide
  • Sulindac sodium
  • Exisulind
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Sulindac (Aflodac; Algocetil; MK231; MK 231; MK-231), belonging to the arylalkanoic acid class of non-steroidal antiinflammatory drugs (NSAIDs), is a non-steroidal COX inhibitor, which potently inhibits prostaglandin synthesis. It has been used in the treatment of acute or chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in the body to the active NSAID, sulindac sulfide, a cyclooxgenase inhibitor that represses ras signaling, and sulindac sulfone, an antitumor agent, following oral administration in vivo.

Biological Activity I Assay Protocols (From Reference)
ln Vitro
TGF-β1-induced epithelial-mesenchymal transition (EMT) is efficiently inhibited by sulindac (MK-231) (500 μM, 48 hours), as evidenced by the overexpression of the epithelial marker E-cadherin and the downregulation of transcription factors and mesenchymal markers [1]. The TGF-β1-enhanced migration and invasion of A549 cells is inhibited by sulindac (500 μM, 48 h) [1]. TGF-β1-induced EMT is more effectively reversed by sulindac (500 μM, 48 h), and SIRT1 overexpression encourages TGF-β1-induced EMT[1].
ln Vivo
Sulindac (MK-231) (15 mg/kg po, bid; sulindac alone); 7.5 mg/kg po, bid; sulindac plus PD-L1)) demonstrated a marked decrease in tumor volume and an increase in CD8+ T cell infiltration. in tumor tissue following combination therapy treatment [2]. By inhibiting the NF-κB signaling pathway, sulindac (15 mg/kg orally twice daily; 7.5 mg/kg orally twice daily; sulindac with PD-L1) can downregulate PD-L1 and reduce exosome P[2]. By downregulating PD-L1 in combination treatment, sulindac (15 mg/kg po, bid; sulindac alone); 7.5 mg/kg po, bid; sulindac in conjunction with PD-L1)) increases the availability of PD-L1 Ab [2]. Prostaglandin E2 (PGE2) is not systemically inhibited by sulindac at low dosages (15 mg/kg po, bid; sulindac alone; 7.5 mg/kg po, bid; sulindac in conjunction with PD-L1)[2].
Cell Assay
Western Blot Analysis[1]
Cell Types: A549 cells
Tested Concentrations: 500 μM
Incubation Duration: 48 h
Experimental Results: Inhibit transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition in A549 cells.

Immunofluorescence[1]
Cell Types: A549 cells
Tested Concentrations: 500 μM
Incubation Duration: 48 h
Experimental Results: Reversed SIRT-1 expression by TGF-β1 and inhibited the TGF-β1-induced cadherin switch.

Cell Migration Assay [1]
Cell Types: A549 cells
Tested Concentrations: 500 μM
Incubation Duration: 48 h
Experimental Results: Inhibited migration, diminished resistance co-treatment with TGF-β1. Cell Invasion Assay[1]
Cell Types: A549 cells
Tested Concentrations: 500 μM
Incubation Duration: 40 h; 48 h
Experimental Results: Could effectively inhibit the TGF- β1-induced increase in invasion by lung cancer cells.
Animal Protocol
Animal/Disease Models: CT26 syngeneic mouse tumor model[2]
Doses: 15 mg/kg; 7.5 mg/kg
Route of Administration: 15 mg/kg, po, bid (sulindac alone); 7.5 mg/kg po, bid (sulindac combination with PD- L1)
Experimental Results: Downregulated PD-L1 through the blockade of NF-κB signaling and modulate the response of pMMR CRC to anti-PD-L1 immunotherapy. Cound effectively inhibit PD-L1 with no significant systematic toxicity.
ADME/Pharmacokinetics
Absorption, Distribution and Excretion
Approximately 90% absorbed in humans following oral administration.
Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk. Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Hepatic metabolism is an important elimination pathway.
Renal cl=68.12 +/- 27.56 mL/min [NORMAL (19-41 yrs)]
Metabolism / Metabolites
Undergoes two major biotransformations: reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Sulindac and its sulfide and sulfone metabolites undergo extensive enterohepatic circulation. Available evidence indicates that the biological activity resides with the sulfide metabolite. Side chain hydroxylation and hydration of the double bond also occur.
Biological Half-Life
The mean half-life of sulindac is 7.8 hours while the mean half-life of the sulfide metabolite is 16.4 hours.
Toxicity/Toxicokinetics
Hepatotoxicity
Chronic therapy with sulindac is associated with a low rate of serum aminotransferase elevations, which are rarely severe and usually self-limited. Clinically apparent acute liver injury from sulindac is well known, but rare (~5 cases in 100,000 prescriptions and ~0.1% of users). Sulindac hepatotoxicity typically presents with fever, rash, nausea and vomiting and abdominal pain arising within a few days or weeks of starting the medication and followed shortly thereafter by jaundice. Occasionally, the onset may be delayed, particularly if therapy is intermittent. The clinical pattern suggests an allergic hepatitis and is somewhat similar to the hepatotoxicity of the sulfonamides. The pattern of serum enzyme elevations is usually hepatocellular or mixed at the onset, but may then become cholestatic. However, recovery is usually rapid once sulindac is stopped. Histology is consistent with an allergic hepatitis with spotty necrosis and marked inflammatory cell infiltration with prominence of eosinophils. In many instances, the features of hypersensitivity (such as facial swelling, desquamating rash, pharyngitis, stomatitis, lymphadenopathy, and hypotension) overshadow the liver injury and are more commonly the cause of death. Sulindac can also cause acute liver injury with a more delayed latency with few or no features of hypersensitivity. These cases are usually cholestatic and can be prolonged and lead to vanishing bile duct syndrome.
Likelihood score: A (well established, although rare cause of clinically apparent liver injury).
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
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.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
Protein Binding
At 1 mcg/ml concentrations, approximately 93% sulindac and 98% of its sulfide metabolite are bound to human serum albumin.
References

[1]. Celecoxib and sulindac inhibit TGF-β1-induced epithelial-mesenchymal transition and suppress lung cancer migration and invasion via downregulation of sirtuin 1. Oncotarget. 2016 Aug 30;7(35):57213-57227.

[2]. Sulindac Modulates the Response of Proficient MMR Colorectal Cancer to Anti-PD-L1 Immunotherapy. Mol Cancer Ther. 2021 Jul;20(7):1295-1304.

Additional Infomation
Sulindac can cause developmental toxicity and female reproductive toxicity according to state or federal government labeling requirements.
Sulindac is a monocarboxylic acid that is 1-benzylidene-1H-indene which is substituted at positions 2, 3, and 5 by methyl, carboxymethyl, and fluorine respectively, and in which the phenyl group of the benzylidene moiety is substituted at the para position by a methylsulfinyl group. It is a prodrug for the corresponding sulfide, a non-steroidal anti-inflammatory drug, used particularly in the treatment of acute and chronic inflammatory conditions. It has a role as a non-steroidal anti-inflammatory drug, an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor, an antineoplastic agent, a non-narcotic analgesic, an antipyretic, an analgesic, a prodrug, a tocolytic agent and an apoptosis inducer. It is a sulfoxide, a monocarboxylic acid and an organofluorine compound. It is functionally related to an acetic acid.
Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that is marketed by Merck under the brand name Clinoril. Like other NSAIDs, it may be used in the treatment of acute or chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in vivo to an active sulfide compound by liver enzymes. There is evidence from some studies that sulindac may be associated with fewer gastrointestinal side effects than other NSAIDs, except for the cyclooxygenase-2 (COX-2) inhibitor drug class. This may be due to the sulfide metabolite undergoing enterohepatic circulation thus maintaining constant blood levels of the compound without inducing gastrointestinal effects, where the drug is excreted in the bile and then reabsorbed from the intestines. While its full mechanism of action is not fully understood, sulindac is thought to primarily mediate its action by inhibiting prostaglandin synthesis by inhibiting COX-1 and COX-2.
Sulindac is a Nonsteroidal Anti-inflammatory Drug. The mechanism of action of sulindac is as a Cyclooxygenase Inhibitor.
Sulindac is a commonly used nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and used predominantly to treat chronic arthritis. Sulindac is a rare, but well established cause of idiosyncratic, clinically apparent drug induced liver disease.
Sulindac is a sulfinylindene derivative prodrug with potential antineoplastic activity. Converted in vivo to an active metabolite, sulindac, a nonsteroidal anti-inflammatory drug (NSAID), blocks cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE), an enzyme that inhibits the normal apoptosis signal pathway; this inhibition permits the apoptotic signal pathway to proceed unopposed, resulting in apoptotic cell death. (NCI04)
A sulfinylindene derivative prodrug whose sulfinyl moiety is converted in vivo to an active NSAID analgesic. Specifically, the prodrug is converted by liver enzymes to a sulfide which is excreted in the bile and then reabsorbed from the intestine. This helps to maintain constant blood levels with reduced gastrointestinal side effects.
See also: Sulindac sodium (is active moiety of).
Drug Indication
For acute or long-term use in the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis.
FDA Label
Mechanism of Action
Sulindac's exact mechanism of action is unknown. Its antiinflammatory effects are believed to be due to inhibition of both COX-1 and COX-2 which leads to the inhibition of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.
Pharmacodynamics
Sulindac is a non-steroidal anti-inflammatory indene derivative, also possessing analgesic and antipyretic activities.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C20H17FO3S
Molecular Weight
356.41
Exact Mass
356.088
CAS #
38194-50-2
Related CAS #
Sulindac sulfide;49627-27-2;Sulindac sodium;63804-15-9;Sulindac-d3;Sulindac sulfone;59973-80-7
PubChem CID
1548887
Appearance
White to yellow solid powder
Density
1.4±0.1 g/cm3
Boiling Point
581.6±50.0 °C at 760 mmHg
Melting Point
182-185°C
Flash Point
305.6±30.1 °C
Vapour Pressure
0.0±1.7 mmHg at 25°C
Index of Refraction
1.673
LogP
3.59
Hydrogen Bond Donor Count
1
Hydrogen Bond Acceptor Count
5
Rotatable Bond Count
4
Heavy Atom Count
25
Complexity
616
Defined Atom Stereocenter Count
0
SMILES
CC\1=C(C2=C(/C1=C\C3=CC=C(C=C3)S(=O)C)C=CC(=C2)F)CC(=O)O
InChi Key
MLKXDPUZXIRXEP-MFOYZWKCSA-N
InChi Code
InChI=1S/C20H17FO3S/c1-12-17(9-13-3-6-15(7-4-13)25(2)24)16-8-5-14(21)10-19(16)18(12)11-20(22)23/h3-10H,11H2,1-2H3,(H,22,23)/b17-9-
Chemical Name
(Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetic acid
Synonyms
Sulindac; Aflodac;MK231; MK 231; Algocetil; MK-231;
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 71 mg/mL (199.2 mM)
Water:<1 mg/mL
Ethanol: 9 mg/mL (25.25 mM)
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.01 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.5 mg/mL (7.01 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.8058 mL 14.0288 mL 28.0576 mL
5 mM 0.5612 mL 2.8058 mL 5.6115 mL
10 mM 0.2806 mL 1.4029 mL 2.8058 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01843179 Withdrawn Drug: Cytarabine
Drug: Sulindac
Acute Myeloid Leukemia Massachusetts General Hospital January 2014 Phase 2
NCT04542135 Recruiting Drug: Sulindac Pill
Drug: Placebo
Breast Cancer Alison Stopeck November 20, 2020 Phase 2
NCT01636128 Withdrawn Drug: difluoromethylornithine
Drug: Sulindac
Focus of Study: Drug Response
Biomarkers, Chemoprevention, Neoplasms
Cancer Prevention Pharmaceuticals, Inc. March 2014 Phase 2
NCT01856322 Terminated Has Results Drug: Sulindac
Drug: Placebo
Colorectal Cancer
Liver Metastasis
National Cancer Institute (NCI) April 2013 Phase 2
Biological Data
  • Transforming growth factor (TGF)-β1-induced sirtuin 1 (SIRT1) expression in lung cancer. A. Endogenous expression of the epithelial-mesenchymal transition (EMT)-related proteins E-cadherin, N-cadherin, and SIRT1 was assessed in non-small cell lung cancer cell lines. B. A549 cells were treated with TGF-β1 (5 or 10 ng/mL) and epidermal growth factor (50 or 100 ng/mL) for 24 h. EMT hallmarks were examined using western blot analysis. Similar data were obtained from three independent experiments.
  • Transforming growth factor (TGF)-β1-induced sirtuin 1 (SIRT1) expression. A. and B. A549 cells were treated with TGF-β1, and SIRT1 mRNA was quantified by real-time polymerase chain reaction in a time or dose dependent manner. The data represent the mean ± SD of three independent experiments. *p < 0.05 compared to the control. C and D. A549 cells were treated with TGF-β1, and the expression of E-cadherin, N-cadherin, and SIRT1 was determined by immunoblotting. E. A549 cells were treated with 5 ng/mL TGF-β1, with or without SB431542 for 24h, and SIRT1 protein levels were examined by immunoblotting. Similar data were obtained from three independent experiments.
  • Celecoxib and sulindac inhibit transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition in A549 cells. A. A549 cells were stimulated with 5 ng/mL TGF-β1 for 2 h and then incubated with 10 μM celecoxib or 500 μM sulindac for 48 h. Cell morphology was examined, and cells were fixed, permeabilized, and stained with anti-SIRT1, E-cadherin, and N-cadherin monoclonal antibody (green); and DAPI (blue). Cells were analyzed by confocal microscopy. All scale bars represent 60 μm. B. Western blot analysis using specific antibodies was performed to examine protein expression in whole cell lysates. Representative images from more than three independent experiments are shown. C. A549 cells were stimulated with 5 ng/mL TGF-β1 for 2 h and then incubated with 10 μM celecoxib or 500 μM sulindac for 48 h. The supernatants were analyzed by gelatin zymography, and cell lysates was subjected to 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis to measure the expression of MMP2 and MMP9. D. Cells were treated with 10 μM celecoxib or 500 μM sulindac in the absence or presence of 5 ng/mL TGF-β1. Cell lysates were then prepared and subjected to immunoblot analysis with antibodies to phosphorylated (p) or total forms of smad 2/3. Immunoblots are representative of at least three independent experiments.
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