Sodium aurothiomalate

Aurothiomalate sodium is a potent and selective oncogenic PKCι signaling inhibitor. Aurothiomalate sodium inhibits tumor cell proliferation and not cell apoptosis. Aurothiomalate sodium is a potent thioredoxin reductase (TrxR) inhibitor. Aurothiomalate sodium, an anti-rheumatoid agent, exhibits potent anti-tumor activity[1][2][3].

Signaling Pathways >> Epigenetics >> PKC

Research Areas >> Cancer

Research Areas >> Inflammation/Immunology

Signaling Pathways >> TGF-beta/Smad >> PKC

PKCι

Aurothiomalate sodium (0.001, 0.01, 0.1, 1, 10, 100, 1000 uM) induces dose-dependent inhibition of anchorage-independent growth in all cell lines tested (A549, H1437, H2170, H460, H510, H187, H1703 and A427 lung cancer cell lines) with IC50s ranging from 300 nM-107 µM. The lung adenocarcinoma (LAC) and small cell lung carcinoma (SCLC) cells tends to be more sensitive and lung adenocarcinomas (LACs) less sensitive to Aurothiomalate sodium[1]. Aurothiomalate sodium (25 uM; 6 hours) suppresses TNFa-induced activation of NF-kB and the expression of NF-kB-targeted proinflammatory genes such as E-selectin and cyclooxygenase-2[3]. Aurothiomalate sodium inhibits non-small lung cancer (NSCLC) growth by binding PKCι and blocking activation of a PKCι-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway[1]. Aurothiomalate sodium inhibits Mek/Erk signaling and decreases proliferative index without effecting tumor apoptosis or vascularization in vivo[1]. Western Blot Analysis[1] Cell Line: Bovine arterial endothelial cells (BAEC) Concentration: 25 uM Incubation Time: 6 hours Result: Suppressed TNFa-induced NF-kB-dependent gene expression in a dose-dependent manner. Did not affect TrxR1 mRNA level in COS7 cells.

Aurothiomalate sodium (2, 6, 20 or 60 mg/kg/day; intramuscular injections; 40 days) exhibits statistically significant inhibition of tumor growth at all concentrations tested in A427 cell tumors because A427 cells are highly responsive[1]. Aurothiomalate sodium (20, 60 mg/kg/day; intramuscular injections; 15 days) shows a statistically significant response (~50% reduction in tumor size) only at the 60 mg/kg dose in H460 tumors because H460 cells are less responsive[1]. Aurothiomalate sodium (60 mg/kg/day; IP; for six weeks) exhibites a decrease in tumor growth in Three-week-old KrasLA2 mice. Aurothiomalate sodium inhibits Kras-mediated bronchioalveolar stem cells (BASCs) expansion and lung tumorigenesis in vivo[2]. Animal Model: 4-6-week-old female nude mice with A427 or H460 cells[1] Dosage: 2, 6, 20 or 60 mg/kg Administration: Intramuscular injections; daily; 40 days Result: Exhibited statistically significant inhibition of tumor growth at all concentrations tested in A427 cell tumors because A427 cells are highly responsive.

[1]. Roderick P Regala, et al. Atypical protein kinase C iota expression and aurothiomalate sensitivity in human lung cancer cells. Cancer Res. 2008 Jul 15;68(14):5888-95.

[2]. Roderick P Regala, et al. Atypical protein kinase C{iota} is required for bronchioalveolar stem cell expansion and lung tumorigenesis. Cancer Res. 2009 Oct 1;69(19):7603-11.

[3]. Atsuko Sakurai, et al. Overexpression of thioredoxin reductase 1 regulates NF-kappa B activation. J Cell Physiol. 2004 Jan;198(1):22-30.

MOLECULAR FORMULA :

C4-H3-Au-O4-S.2Na

MOLECULAR WEIGHT :

390.08

WISWESSER LINE NOTATION :

OVYVO&1S-AU- &-NA- 2

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

5500 ug/kg

TOXIC EFFECTS :

Peripheral Nerve and Sensation - recording from peripheral motor nerve Kidney, Ureter, Bladder - renal function tests depressed Blood - thrombocytopenia

REFERENCE :

ARHEAW Arthritis and Rheumatism. (Arthritis Foundation, 1314 Spring St., NW, Atlanta, GA 30309) V.1- 1958- Volume(issue)/page/year: 19,936,1976

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

182 ug/kg

TOXIC EFFECTS :

Skin and Appendages - dermatitis, other (after systemic exposure)

REFERENCE :

BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- Volume(issue)/page/year: 2,1294,1976

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

2700 ug/kg/4W-I

TOXIC EFFECTS :

Brain and Coverings - changes in circulation (hemorrhage, thrombosis, etc.)

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 11,235,1984

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

20 mg/kg/1Y

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - aggression Kidney, Ureter, Bladder - proteinuria

REFERENCE :

ARPAAQ Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50; V.70-99, 1960-75. For publisher information, see APLMAS. Volume(issue)/page/year: 96,133,1973

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

5 mg/kg/13W

TOXIC EFFECTS :

Blood - hemorrhage Blood - thrombocytopenia Musculoskeletal - changes in teeth and supporting structures

REFERENCE :

JAMAAP JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- Volume(issue)/page/year: 133,754,1947

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

600 ug/kg/1W-I

TOXIC EFFECTS :

Lungs, Thorax, or Respiration - fibrosis (interstitial) Liver - jaundice, cholestatic Nutritional and Gross Metabolic - body temperature increase

REFERENCE :

JRSMD9 Journal of the Royal Society of Medicine. (Oxford Univ. Press, Walton St., Oxford OX2 6DP, UK) V.71- 1978- Volume(issue)/page/year: 77,960,1984

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

3366 ug/kg/2W

TOXIC EFFECTS :

Peripheral Nerve and Sensation - flaccid paralysis without anesthesia (usually neuromuscular blockage) Behavioral - muscle weakness

REFERENCE :

NEURAI Neurology. (Modern Medicine Pub., Inc., 1 E. First St., Duluth, MN 55802) V.1- 1951- Volume(issue)/page/year: 20,455,1970

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

12500 ug/kg/7W-I

TOXIC EFFECTS :

Brain and Coverings - encephalitis Peripheral Nerve and Sensation - fasciculations Peripheral Nerve and Sensation - structural change in nerve or sheath

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 11,233,1984

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

7857 ug/kg/11W-I

TOXIC EFFECTS :

Skin and Appendages - dermatitis, other (after systemic exposure) Immunological Including Allergic - uncharacterized

REFERENCE :

BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- Volume(issue)/page/year: 286,1547,1983

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human - child

DOSE/DURATION :

11900 ug/kg/18W-I

TOXIC EFFECTS :

Biochemical - Metabolism (Intermediary) - other

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 13,224,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human

DOSE/DURATION :

9750 ug/kg/23W-I

TOXIC EFFECTS :

Blood - changes in cell count (unspecified) Blood - aplastic anemia Blood - other changes

REFERENCE :

BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- Volume(issue)/page/year: 1,1266,1976

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

12 mg/kg

TOXIC EFFECTS :

Blood - thrombocytopenia

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 13,225,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

1600 ug/kg/3W-I

TOXIC EFFECTS :

Liver - hepatitis (hepatocellular necrosis), diffuse Blood - agranulocytosis

REFERENCE :

ANZJB8 Australian and New Zealand Journal of Medicine. (Modern Medicine of Australia Pty., Ltd., 100 Pacific Highway, North Sydney, 2060, Australia) V.1- 1971- Volume(issue)/page/year: 16,72,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

7 mg/kg/7W-I

TOXIC EFFECTS :

Blood - thrombocytopenia

REFERENCE :

JRHUA9 Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- Volume(issue)/page/year: 12,180,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

7857 ug/kg/11W-I

TOXIC EFFECTS :

Immunological Including Allergic - uncharacterized

REFERENCE :

BJRHDF British Journal of Rheumatology. (Bailliere Tindall, 33 The Avenue, Eastborn BN21 3UN, UK) Volume(issue)/page/year: 24,367,1985

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

303 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: 6,208,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

440 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: 6,208,1982

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

185 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

PSEBAA Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- Volume(issue)/page/year: 49,121,1942

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

930 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: 6,208,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

855 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: 6,208,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

800 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

VTPHAK Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- Volume(issue)/page/year: 15(Suppl 5),1,1978 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

75 mg/kg

SEX/DURATION :

female 4-6 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - other effects to embryo

REFERENCE :

JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 214,250,1980

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

75 mg/kg

SEX/DURATION :

female 13-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - biochemical and metabolic

REFERENCE :

JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 214,250,1980

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

250 mg/kg

SEX/DURATION :

female 6-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - Central Nervous System Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :

VTPHAK Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- Volume(issue)/page/year: 15(Suppl 5),89,1978

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

100 mg/kg

SEX/DURATION :

female 9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

REFERENCE :

CBINA8 Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- Volume(issue)/page/year: 58,149,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

900 mg/kg

SEX/DURATION :

female 6-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)

REFERENCE :

VTPHAK Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- Volume(issue)/page/year: 15(Suppl 5),89,1978

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

257 mg/kg

SEX/DURATION :

female 6-13 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

REFERENCE :

VTPHAK Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- Volume(issue)/page/year: 15(Suppl 5),97,1978 *** REVIEWS *** TOXICOLOGY REVIEW MDCHAG Medicinal Chemistry: A Series of Monographs. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1963- Volume(issue)/page/year: 13(1),209,1974 TOXICOLOGY REVIEW PTPAD4 Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and Metabolic Inhibitors. (Oxford, UK) V.1-2, 1976-78. For publisher information, see PHTHDT. Volume(issue)/page/year: 1,119,1976 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X6050 No. of Facilities: 14 (estimated) No. of Industries: 1 No. of Occupations: 2 No. of Employees: 731 (estimated) No. of Female Employees: 366 (estimated)