Sulindac

Sulindac is a non-steroidal antiinflammatory agent, acts as a COX-2 inhibitor, and inhibits overexpression of COX-2.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Immunology/Inflammation >> COX

Research Areas >> Inflammation/Immunology

COX-2

Autophagy

Sulindac is a non-steroidal antiinflammatory agent, acts as a COX-2 inhibitor, and inhibits overexpression of COX-2[1]. Sulindac (0.1 mM to 0.5 mM) causes limited death in both p53 wt and p53 null HCT116 cells, but in combination with vitamin C, it dramatically increases almost 5-fold in cell death in p53 wt HCT116 cells relative to the vitamin C alone, and such an effect is involving caspase activation and p53 function in these cells, and via ROS-mediated pathway. Sulindac combined with vitamin C significantly increases PUMA levels, but shows no effect on Bim, Bcl-2 and Mcl-1 levels[2]. Sulindac (500 μM) in combination with celecoxib blocks transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition, migration and invasion in A549 cells. The combination also suppresses involvement of sirtuin 1 (SIRT1) in transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT)[3].

Sulindac (0.5 ± 0.1 mg/day) decreases COX, modolates PGE2 levels and prevents tumor formation in the Min mice[1].

Cells are treated with Sulindac and/or vitamin C at the indicated doses for 48 h, and cell viability is analyzed using a trypan blue exclusion assay. For the annexin V staining assay, cells are treated with 0.5 mM Sulindac and/or 0.5 mM vitamin C for 48 h. The cells are then trypsinized, washed with PBS, stained with propidium iodide (PI) and FITC-labeled annexin V for 30 min, and analyzed by flow cytometry using a fluorescence-activated cell sorter[2].

Mice[1] Female C57BL16J-Min/+ (Min) mice at 5 weeks of age are used in the assay. Beginning at 5-6 weeks of age, 10 Min mice are fed a low-fat AIN-76A chow diet modified with 0.001% ethoxyquin and Sulindac, 0.5 ± 0.1 mg/day (0.05 mg/kcal/day or approximately 160 ppm) in drinking water. As controls, 9 Min mice and 5 C57BL/6J-+/+ non-affected littermates (+/+) are fed AIN-76A diet without Sulindac. Animals are checked daily for signs of distress or anemia. Animals and their food are weighed twice weekly. During the course of the experiment, there is no difference in body weight or food consumption among the various study groups. No toxicity is observed in the Min/Sulindac group. At 110 days of age, all mice are euthanized by CO2 inhalation, and their intestinal tracts are removed from esophagus to distal rectum, opened, flushed with saline, and examined under ×3 magnification to obtain tumor counts. Tumors are counted by an individual blinded to the animal's genetic status and treatment. Multiple samples of grossly normal, full-thickness bowel are harvested from the mid small intestine and either frozen in liquid nitrogen or fixed in 10% formalin for histological examination. All samples used for the analyses in this study are taken from mid small intestine[1].

[1]. Boolbol SK, et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996 Jun 1;56(11):2556-60.

[2]. Gong EY, et al. Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells. Toxicol Lett. 2016 Sep 6;258:126-133.

[3]. Cha BK, et al. 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.

4-Acetamidophenol | Aspirin | Paradol | Ginsenoside Rg3 | Ginsenoside Compound K | Xanthohumol | Ibuprofen | Diclofenac | NS-398 | Meloxicam | Flufenamic Acid | Epicatechin | Salicylic acid | ketoprofen | Naproxen

MOLECULAR FORMULA :

C20-H17-F-O3-S

MOLECULAR WEIGHT :

356.43

WISWESSER LINE NOTATION :

L56 BYJ BU1R DSO&1& C1 D1VQ GF

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

43 mg/kg/10D-I

TOXIC EFFECTS :

Lungs, Thorax, or Respiration - other changes Liver - liver function tests impaired Blood - leukopenia

REFERENCE :

JAMAAP JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- Volume(issue)/page/year: 244,269,1980

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

112 mg/kg/2W-I

TOXIC EFFECTS :

Gastrointestinal - nausea or vomiting Liver - hepatitis (hepatocellular necrosis), diffuse Nutritional and Gross Metabolic - body temperature increase

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 10,512,1983

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

8 mg/kg/10H-I

TOXIC EFFECTS :

Behavioral - anorexia (human) Behavioral - muscle contraction or spasticity Gastrointestinal - hypermotility, diarrhea

REFERENCE :

JCGADC Journal of Clinical Gastroenterology. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) Volume(issue)/page/year: 8,569,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

34 mg/kg/6D-I

TOXIC EFFECTS :

Nutritional and Gross Metabolic - changes in potassium

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 13,1084,1986

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

264 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 30,1398,1980

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

289 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 13,637,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

336 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 13,637,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

507 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NIIRDN Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) Volume(issue)/page/year: 6,APP-6,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

305 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 13,637,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

398 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 13,637,1982 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

4 mg/kg

SEX/DURATION :

female 13 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue)

REFERENCE :

JCGBDF Journal of Craniofacial Genetics and Developmental Biology. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- Volume(issue)/page/year: 10,83,1990

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

DOSE :

4 mg/kg

SEX/DURATION :

female 13 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue)

REFERENCE :

JCGBDF Journal of Craniofacial Genetics and Developmental Biology. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- Volume(issue)/page/year: 10,83,1990 *** REVIEWS *** TOXICOLOGY REVIEW DSMJAA Delaware Medical Journal. (Medical Soc. of Delaware, 1925 Lovering Ave., Wilmington, DE 19806) V.32(2)- 1960- Volume(issue)/page/year: 53,193,1981 TOXICOLOGY REVIEW REPTED Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- Volume(issue)/page/year: 9,7,1995 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X5356 No. of Facilities: 81 (estimated) No. of Industries: 2 No. of Occupations: 9 No. of Employees: 4344 (estimated) No. of Female Employees: 1829 (estimated)