THIORIDAZINE

Thioridazine, an antagonist of the dopamine receptor D2 family proteins, exhibits potent anti-psychotic and anti-anxiety activities. Thioridazine is also a potent inhibitor of PI3K-Akt-mTOR signaling pathways with anti-angiogenic effect. Thioridazine shows antiproliferative and apoptosis induction effects in various types of cancer cells, with specificity on targeting cancer stem cells (CSCs)[1][2][3][4].

Signaling Pathways >> Apoptosis >> Apoptosis

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> GPCR/G Protein >> Dopamine Receptor

Signaling Pathways >> Neuronal Signaling >> Dopamine Receptor

Research Areas >> Neurological Disease

Signaling Pathways >> GPCR/G Protein >> 5-HT Receptor

Signaling Pathways >> Neuronal Signaling >> 5-HT Receptor

Signaling Pathways >> Anti-infection >> Bacterial

Thioridazine (0.01-100 μM; 48 h) reduces the cell viability of NCI-N87 and AGS cells in a concentration-dependent manner[2]. Thioridazine (15 μM; 24 h) reduces cell viability of the cervical (HeLa, Caski and C33A) and endometrial (HEC-1-A and KLE) cancer cells[4]. Thioridazine (1-15 μM; 24-48 h) induces gastric cancer cell death via the mitochondrial apoptosis pathway and mitochondrial pathway[2]. Thioridazine (15 μM; 24 h) modulates the regulation of cell cycle progression by interfering with the PI3K/Akt pathway and induces G1 cell cycle arrest in cervical and endometrial cancer cells [4]. Thioridazine inhibits the growth of antibiotic-sensitive and multidrug-resistant strains of A. baumannii[3]. Cell Viability Assay[1] Cell Line: NCI-N87 and AGS cells. Concentration: 0.01, 0.1, 0.5, 1, 5, 10, 20, 50, 100 μM. Incubation Time: 48 hours. Result: Exhibited cytotoxicity in gastric cancer cells. Western Blot Analysis[1] Cell Line: NCI-N87 and AGS cells Concentration: 1, 5, 10, 15 μM. Incubation Time: 24, 48 hours. Result: Downregulated the precursors of caspase-9, caspase-8 and caspase-3.

Thioridazine (25 mg/kg; i.p. every 3 days for 3 weeks) extends the survival of tumor-bearing mice and reduces the number of pluripotent embryonal carcinoma (EC) cells within tumors[5]. Thioridazine (1.0-5.0 mg/kg; s.c.) reduces oral behavior and selectively blocks repetitive head bobbing[1]. Animal Model: Nude and Rag2KO mice were injected with iPS cells or NT2D1 cells[5] Dosage: 25 mg/kg. Administration: I.p. every 3 days for 3 weeks. Result: Reduced the number of OCT4-expressing cells within malignant teratocarcinomas and extended the survival of tumor-bearing mice. With no effect on fertility.

[1]. Tschanz JT, et, al. Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy. Pharmacol Biochem Behav. 1988 Nov;31(3):519-22.

[2]. Mu J, et, al. Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer. Oncol Rep. 2014 May;31(5):2107-14.

[3]. Kang S, et, al. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 2012 Sep;17(9):989-97.

[4]. Loehr AR, et, al. Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors. Cancers (Basel). 2021 Apr 23;13(9):2045.

MOLECULAR FORMULA :

C21-H26-N2-S2

MOLECULAR WEIGHT :

370.61

WISWESSER LINE NOTATION :

T C666 BN ISJ ES1 B2- BT6NTJ A1

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

43 mg/kg

TOXIC EFFECTS :

Cardiac - other changes Lungs, Thorax, or Respiration - acute pulmonary edema Lungs, Thorax, or Respiration - cyanosis

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - child

DOSE/DURATION :

28 mg/kg/2W-I

TOXIC EFFECTS :

Behavioral - muscle contraction or spasticity

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

14500 mg/kg/15Y-I

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - visual field changes Sense Organs and Special Senses (Eye) - retinal changes (pigmentary depositions, retinitis, other)

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human

DOSE/DURATION :

43 mg/kg

TOXIC EFFECTS :

Vascular - regional or general arteriolar or venous dilation Lungs, Thorax, or Respiration - chronic pulmonary edema Blood - hemorrhage

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - child

DOSE/DURATION :

25 mg/kg

TOXIC EFFECTS :

Cardiac - change in rate Behavioral - toxic psychosis

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human

DOSE/DURATION :

24 mg/kg

TOXIC EFFECTS :

Autonomic Nervous System - parasympatholytic

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

5214 mg/kg/5Y-I

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - retinal changes (pigmentary depositions, retinitis, other)

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

995 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

150 mg/kg

TOXIC EFFECTS :

Behavioral - anticonvulsant Behavioral - antipsychotic

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

640 mg/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - ptosis Autonomic Nervous System - central sympatholytic Behavioral - alteration of classical conditioning

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

71 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

385 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

65 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

310 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

53 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

1200 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

26 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

3040 mg/kg/22W-I

TOXIC EFFECTS :

Cardiac - EKG changes not diagnostic of specified effects

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

10 mg/kg

SEX/DURATION :

male 7 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - impotence

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

30 mg/kg

SEX/DURATION :

male 7 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - impotence

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

3214 ug/kg

SEX/DURATION :

male 3 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - impotence

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

80 mg/kg

SEX/DURATION :

female 1-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

100 mg/kg

SEX/DURATION :

female 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - other measures of fertility

MUTATION DATA

TEST SYSTEM :

Insect - Drosophila melanogaster

DOSE/DURATION :

100 mg/L

REFERENCE :

IJEBA6 Indian Journal of Experimental Biology. (Publications & Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- Volume(issue)/page/year: 11,403,1973 *** REVIEWS *** TOXICOLOGY REVIEW JMSCA9 Journal of Mental Science. (London, UK) V.4-108, 1857-1962. For publisher information, see BJPYAJ. Volume(issue)/page/year: 106,755,1960 TOXICOLOGY REVIEW IDPYAK Industrial Pharmacology. (Mount Kisco, NY) V.1-3, 1974-79. Discontinued. Volume(issue)/page/year: 1,203,1974 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X5668 No. of Facilities: 35 (estimated) No. of Industries: 1 No. of Occupations: 1 No. of Employees: 430 (estimated) No. of Female Employees: 239 (estimated)