Arsenic trioxide

Identification

Summary

Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy.

Brand Names
Trisenox
Generic Name
Arsenic trioxide
DrugBank Accession Number
DB01169
Background

Arsenic trioxide is a chemotherapeutic agent of idiopathic function used to treat leukemia that is unresponsive to first line agents. It is suspected that arsenic trisulfide induces cancer cells to undergo apoptosis. In general, arsenic is known to be a naturally toxic substance capable of eliciting a variety of dangerous adverse effects. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 197.84
Monoisotopic: 197.827934
Chemical Formula
As2O3
Synonyms
  • Acide Arsenieux
  • Anhydride Arsenieux
  • Arsenic Blanc
  • Arsenic oxide
  • Arsenic trioxide
  • Arsenic(III) oxide
  • arsénico trióxido
  • Arsenigen Saure
  • Arsenolite
  • Arsenous oxide
  • Arsenous oxide anhydride
  • Diarsenic oxide
  • Diarsenic trioxide
  • White arsenic

Pharmacology

Indication

For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatAcute promyelocytic leukemia (apl)Regimen in combination with: Tretinoin (DB00755)••••••••••••••••• •••••••••
Used in combination to treatAcute promyelocytic leukemia (apl)Regimen in combination with: Tretinoin (DB00755)••••••••••••••••• •••••••••• •••••••• •••••••••••••
Treatment ofRefractory acute promyelocytic leukemia•••••••••••••••••••• •••••••••••••
Treatment ofRefractory acute promyelocytic leukemia••••••••••••
Treatment ofRelapsed acute promyelocytic leukemia•••••••••••••••••••• •••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.

Mechanism of action

The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis.

TargetActionsOrganism
AInhibitor of nuclear factor kappa-B kinase subunit beta
inducer
Humans
AThioredoxin reductase 1, cytoplasmic
inhibitor
Humans
ATranscription factor AP-1
inducer
Humans
AG1/S-specific cyclin-D1
antagonist
Humans
AMitogen-activated protein kinase 3
inducer
Humans
AMitogen-activated protein kinase 1
inducer
Humans
URAC-alpha serine/threonine-protein kinase
inducer
Humans
UCyclin-dependent kinase inhibitor 1Not AvailableHumans
UHistone deacetylase 1Not AvailableHumans
UProtein PMLNot AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

75% bound

Metabolism

Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide.2 Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question.2

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Route of elimination

Trivalent arsenic is mostly methylated in humans and excreted in urine.

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Symptoms of overdose include convulsions, muscle weakness and confusion.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Arsenic trioxide which could result in a higher serum level.
AbaloparatideThe risk or severity of adverse effects can be increased when Arsenic trioxide is combined with Abaloparatide.
AbataceptThe risk or severity of adverse effects can be increased when Arsenic trioxide is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Arsenic trioxide.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Arsenic trioxide.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Arsenic Trioxide AccordInjection, solution, concentrate1 mg/mlIntravenousAccord Healthcare S.L.U.2020-12-16Not applicableEU flag
Arsenic Trioxide AccordInjection, solution, concentrate1 mg/mlIntravenousAccord Healthcare S.L.U.2020-12-16Not applicableEU flag
Arsenic Trioxide AccordInjection, solution, concentrate1 mg/mlIntravenousAccord Healthcare S.L.U.2020-12-16Not applicableEU flag
Arsenic Trioxide for InjectionSolution2 mg / mLIntravenousEugia Pharma Inc.Not applicableNot applicableCanada flag
Arsenic Trioxide for InjectionSolution1 mg / mLIntravenousSterimax Inc2019-12-20Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Arsenic TrioxideInjection, solution2 mg/1mLIntravenousAuroMedics Pharma LLC2021-10-15Not applicableUS flag
Arsenic trioxideInjection, solution2 mg/1mLIntravenousZydus Lifesciences Limited2019-09-03Not applicableUS flag
Arsenic TrioxideInjection, solution1 mg/1mLIntravenousSintetica US LLC2023-11-09Not applicableUS flag
Arsenic TrioxideInjection2 mg/1mLIntravenousIngenus Pharmaceuticals, LLC2021-01-27Not applicableUS flag
Arsenic trioxideInjection, solution1 mg/1mLIntravenousZydus Pharmaceuticals USA Inc.2018-11-14Not applicableUS flag

Categories

ATC Codes
L01XX27 — Arsenic trioxide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of inorganic compounds known as metalloid oxides. These are inorganic compounds containing an oxygen atom of an oxidation state of -2, in which the heaviest atom bonded to the oxygen is a metalloid.
Kingdom
Inorganic compounds
Super Class
Mixed metal/non-metal compounds
Class
Metalloid organides
Sub Class
Metalloid oxides
Direct Parent
Metalloid oxides
Alternative Parents
Metalloid salts / Inorganic oxides / Inorganic arsenic compounds
Substituents
Inorganic arsenic compound / Inorganic metalloid salt / Inorganic oxide / Metalloid oxide
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
S7V92P67HO
CAS number
1327-53-3
InChI Key
IKWTVSLWAPBBKU-UHFFFAOYSA-N
InChI
InChI=1S/As2O3/c3-1-5-2-4
IUPAC Name
diarsorosooxidane
SMILES
O=[As]O[As]=O

References

General References
  1. Lu J, Chew EH, Holmgren A: Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93. Epub 2007 Jul 18. [Article]
  2. European Public Assessment Report: Trisenox [Link]
KEGG Drug
D02106
PubChem Compound
261004
PubChem Substance
46506448
ChemSpider
229103
RxNav
18330
ChEMBL
CHEMBL1200978
Therapeutic Targets Database
DNC000255
PharmGKB
PA448486
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Arsenic_trioxide
MSDS
Download (78.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Promyelocytic Leukemia1
4CompletedTreatmentChildhood Acute Promyelocytic Leukemia (M3)1
4Unknown StatusTreatmentAcute Promyelocytic Leukemia1
4Unknown StatusTreatmentRefractory Acute Promyelocytic Leukemia / Relapsed Acute Promyelocytic Leukemia1
3Active Not RecruitingTreatmentAcute Promyelocytic Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Akorn Inc.
  • Cell Therapeutics Inc.
  • Cephalon Inc.
  • CP Pharmaceuticals Ltd.
  • Spectrum Pharmaceuticals
  • TTY Biopharm Co. Ltd.
Dosage Forms
FormRouteStrength
InjectionIntravenous1 mg/1mL
InjectionIntravenous2 mg/1mL
Injection, solutionIntravenous1 mg/1mL
Injection, solutionIntravenous2 mg/2mL
SolutionIntravenous1 mg / mL
SolutionIntravenous2 mg / mL
Injection, solution, concentrateIntravenous
InjectionIntravenous
Injection, solution, concentrateIntravenous10 mg/10ml
Injection, solutionIntravenous2 mg/ml
Injection, solution, concentrateIntravenous1 MG/ML
Injection, solutionIntravenous2 mg/1mL
Injection, solution, concentrateIntravenous2 mg/ml
Injection, solution, concentrateIntravenous; Parenteral1 MG/ML
Injection, solution, concentrateIntravenous; Parenteral2 MG/ML
SolutionIntravenous10 mg / 10 mL
SolutionIntravenous12 mg / 6 mL
Injection, solution, concentrateIntravenous1 mg/1ml
SolutionIntravenous1.000 mg
SolutionIntravenous1 mg/1ml
Prices
Unit descriptionCostUnit
Trisenox 10 mg/10 ml ampule43.58USD ml
Arsenic trioxide powder2.59USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6723351No2004-04-202018-11-10US flag
US6855339No2005-02-152018-11-10US flag
US6861076No2005-03-012018-11-10US flag
US6884439No2005-04-262018-11-10US flag
US6982096No2006-01-032018-11-10US flag
US8273379No2012-09-252018-11-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1.7E+004 mg/L (at 16 °C)SHIU,WY ET AL. (1990)
Predicted Properties
PropertyValueSource
logP1.07Chemaxon
pKa (Strongest Basic)-6Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area43.37 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity4.24 m3·mol-1Chemaxon
Polarizability6.91 Å3Chemaxon
Number of Rings0Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9839
Blood Brain Barrier+0.9549
Caco-2 permeable-0.526
P-glycoprotein substrateNon-substrate0.8227
P-glycoprotein inhibitor INon-inhibitor0.9138
P-glycoprotein inhibitor IINon-inhibitor0.9925
Renal organic cation transporterNon-inhibitor0.9297
CYP450 2C9 substrateNon-substrate0.9036
CYP450 2D6 substrateNon-substrate0.829
CYP450 3A4 substrateNon-substrate0.7462
CYP450 1A2 substrateNon-inhibitor0.7393
CYP450 2C9 inhibitorNon-inhibitor0.8625
CYP450 2D6 inhibitorNon-inhibitor0.9133
CYP450 2C19 inhibitorNon-inhibitor0.7968
CYP450 3A4 inhibitorNon-inhibitor0.9567
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9743
Ames testNon AMES toxic0.5978
CarcinogenicityNon-carcinogens0.5984
BiodegradationReady biodegradable0.8156
Rat acute toxicity2.5942 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8253
hERG inhibition (predictor II)Non-inhibitor0.9812
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0a4j-1900000000-b52d2944e92e83f317b5
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-0900000000-83b0e63390fb3ae9b935
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-0900000000-f7f99f562877db6564db
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0900000000-3a2914da9d0d57aacefb
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
General Function
Scaffold protein binding
Specific Function
Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or oth...
Gene Name
IKBKB
Uniprot ID
O14920
Uniprot Name
Inhibitor of nuclear factor kappa-B kinase subunit beta
Molecular Weight
86563.245 Da
References
  1. Ouyang W, Ma Q, Li J, Zhang D, Liu ZG, Rustgi AK, Huang C: Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res. 2005 Oct 15;65(20):9287-93. [Article]
  2. Ouyang W, Li J, Ma Q, Huang C: Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis. 2006 Apr;27(4):864-73. Epub 2005 Dec 29. [Article]
  3. Ouyang W, Zhang D, Ma Q, Li J, Huang C: Cyclooxygenase-2 induction by arsenite through the IKKbeta/NFkappaB pathway exerts an antiapoptotic effect in mouse epidermal Cl41 cells. Environ Health Perspect. 2007 Apr;115(4):513-8. Epub 2006 Dec 14. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thioredoxin-disulfide reductase activity
Specific Function
Isoform 1 may possess glutaredoxin activity as well as thioredoxin reductase activity and induces actin and tubulin polymerization, leading to formation of cell membrane protrusions. Isoform 4 enha...
Gene Name
TXNRD1
Uniprot ID
Q16881
Uniprot Name
Thioredoxin reductase 1, cytoplasmic
Molecular Weight
70905.58 Da
References
  1. Lu J, Chew EH, Holmgren A: Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93. Epub 2007 Jul 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
General Function
Transcriptional activator activity, rna polymerase ii transcription factor binding
Specific Function
Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expre...
Gene Name
JUN
Uniprot ID
P05412
Uniprot Name
Transcription factor AP-1
Molecular Weight
35675.32 Da
References
  1. Muscarella DE, Bloom SE: Differential activation of the c-Jun N-terminal kinase pathway in arsenite-induced apoptosis and sensitization of chemically resistant compared to susceptible B-lymphoma cell lines. Toxicol Sci. 2002 Jul;68(1):82-92. [Article]
  2. Dong Z: The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect. 2002 Oct;110 Suppl 5:757-9. [Article]
  3. Drobna Z, Jaspers I, Thomas DJ, Styblo M: Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals. FASEB J. 2003 Jan;17(1):67-9. Epub 2002 Nov 15. [Article]
  4. Li J, Gorospe M, Barnes J, Liu Y: Tumor promoter arsenite stimulates histone H3 phosphoacetylation of proto-oncogenes c-fos and c-jun chromatin in human diploid fibroblasts. J Biol Chem. 2003 Apr 11;278(15):13183-91. Epub 2003 Jan 23. [Article]
  5. Kietzmann T, Samoylenko A, Immenschuh S: Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. J Biol Chem. 2003 May 16;278(20):17927-36. Epub 2003 Mar 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Transcription factor binding
Specific Function
Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S t...
Gene Name
CCND1
Uniprot ID
P24385
Uniprot Name
G1/S-specific cyclin-D1
Molecular Weight
33728.74 Da
References
  1. Hyun Park W, Hee Cho Y, Won Jung C, Oh Park J, Kim K, Hyuck Im Y, Lee MH, Ki Kang W, Park K: Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis. Biochem Biophys Res Commun. 2003 Jan 3;300(1):230-5. [Article]
  2. Ouyang W, Ma Q, Li J, Zhang D, Liu ZG, Rustgi AK, Huang C: Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res. 2005 Oct 15;65(20):9287-93. [Article]
  3. Ouyang W, Li J, Ma Q, Huang C: Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis. 2006 Apr;27(4):864-73. Epub 2005 Dec 29. [Article]
  4. Hwang BJ, Utti C, Steinberg M: Induction of cyclin D1 by submicromolar concentrations of arsenite in human epidermal keratinocytes. Toxicol Appl Pharmacol. 2006 Dec 1;217(2):161-7. Epub 2006 Aug 11. [Article]
  5. Ouyang W, Li J, Zhang D, Jiang BH, Huang DC: PI-3K/Akt signal pathway plays a crucial role in arsenite-induced cell proliferation of human keratinocytes through induction of cyclin D1. J Cell Biochem. 2007 Jul 1;101(4):969-78. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
General Function
Phosphatase binding
Specific Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK ca...
Gene Name
MAPK3
Uniprot ID
P27361
Uniprot Name
Mitogen-activated protein kinase 3
Molecular Weight
43135.16 Da
References
  1. Fauconneau B, Petegnief V, Sanfeliu C, Piriou A, Planas AM: Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. J Neurochem. 2002 Dec;83(6):1338-48. [Article]
  2. Jung DK, Bae GU, Kim YK, Han SH, Choi WS, Kang H, Seo DW, Lee HY, Cho EJ, Lee HW, Han JW: Hydrogen peroxide mediates arsenite activation of p70(s6k) and extracellular signal-regulated kinase. Exp Cell Res. 2003 Oct 15;290(1):144-54. [Article]
  3. Tanaka-Kagawa T, Hanioka N, Yoshida H, Jinno H, Ando M: Arsenite and arsenate activate extracellular signal-regulated kinases 1/2 by an epidermal growth factor receptor-mediated pathway in normal human keratinocytes. Br J Dermatol. 2003 Dec;149(6):1116-27. [Article]
  4. Felix K, Manna SK, Wise K, Barr J, Ramesh GT: Low levels of arsenite activates nuclear factor-kappaB and activator protein-1 in immortalized mesencephalic cells. J Biochem Mol Toxicol. 2005;19(2):67-77. [Article]
  5. Mousa SA, O'Connor L, Rossman TG, Block E: Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds. Carcinogenesis. 2007 May;28(5):962-7. Epub 2006 Dec 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
General Function
Rna polymerase ii carboxy-terminal domain kinase activity
Specific Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK ca...
Gene Name
MAPK1
Uniprot ID
P28482
Uniprot Name
Mitogen-activated protein kinase 1
Molecular Weight
41389.265 Da
References
  1. Dong Z: The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect. 2002 Oct;110 Suppl 5:757-9. [Article]
  2. He Z, Ma WY, Liu G, Zhang Y, Bode AM, Dong Z: Arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2, and p90 ribosomal S6 kinase 2 but not mitogen- and stress-activated protein kinase 1. J Biol Chem. 2003 Mar 21;278(12):10588-93. Epub 2003 Jan 14. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Protein serine/threonine/tyrosine kinase activity
Specific Function
AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, ...
Gene Name
AKT1
Uniprot ID
P31749
Uniprot Name
RAC-alpha serine/threonine-protein kinase
Molecular Weight
55686.035 Da
References
  1. Fauconneau B, Petegnief V, Sanfeliu C, Piriou A, Planas AM: Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. J Neurochem. 2002 Dec;83(6):1338-48. [Article]
  2. He Z, Ma WY, Liu G, Zhang Y, Bode AM, Dong Z: Arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2, and p90 ribosomal S6 kinase 2 but not mitogen- and stress-activated protein kinase 1. J Biol Chem. 2003 Mar 21;278(12):10588-93. Epub 2003 Jan 14. [Article]
  3. Ivanov VN, Hei TK: Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene. 2005 Jan 20;24(4):616-26. [Article]
  4. Wang ZX, Jiang CS, Liu L, Wang XH, Jin HJ, Wu Q, Chen Q: The role of Akt on arsenic trioxide suppression of 3T3-L1 preadipocyte differentiation. Cell Res. 2005 May;15(5):379-86. [Article]
  5. Tsou TC, Tsai FY, Hsieh YW, Li LA, Yeh SC, Chang LW: Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase. Toxicol Appl Pharmacol. 2005 Nov 1;208(3):277-84. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
May be involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739).
Specific Function
Cyclin binding
Gene Name
CDKN1A
Uniprot ID
P38936
Uniprot Name
Cyclin-dependent kinase inhibitor 1
Molecular Weight
18119.145 Da
References
  1. Huang HS, Liu ZM, Hong DY: Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes. Toxicol Appl Pharmacol. 2010 Apr 15;244(2):234-41. doi: 10.1016/j.taap.2009.12.037. Epub 2010 Jan 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transcription regulatory region sequence-specific dna binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC1
Uniprot ID
Q13547
Uniprot Name
Histone deacetylase 1
Molecular Weight
55102.615 Da
References
  1. Huang HS, Liu ZM, Hong DY: Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes. Toxicol Appl Pharmacol. 2010 Apr 15;244(2):234-41. doi: 10.1016/j.taap.2009.12.037. Epub 2010 Jan 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma-irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration.
Specific Function
Cobalt ion binding
Gene Name
PML
Uniprot ID
P29590
Uniprot Name
Protein PML
Molecular Weight
97549.475 Da
References
  1. Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de The H, Chen SJ, Chen Z: Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science. 2010 Apr 9;328(5975):240-3. doi: 10.1126/science.1183424. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Noreault TL, Kostrubsky VE, Wood SG, Nichols RC, Strom SC, Trask HW, Wrighton SA, Evans RM, Jacobs JM, Sinclair PR, Sinclair JF: Arsenite decreases CYP3A4 and RXRalpha in primary human hepatocytes. Drug Metab Dispos. 2005 Jul;33(7):993-1003. Epub 2005 Apr 15. [Article]
  2. Mann KK, Padovani AM, Guo Q, Colosimo AL, Lee HY, Kurie JM, Miller WH Jr: Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation. J Clin Invest. 2005 Oct;115(10):2924-33. Epub 2005 Sep 22. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Shooshtary S, Behtash S, Nafisi S: Arsenic trioxide binding to serum proteins. J Photochem Photobiol B. 2015 Jul;148:31-36. doi: 10.1016/j.jphotobiol.2015.03.001. Epub 2015 Apr 1. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Kauffmann HM, Pfannschmidt S, Zoller H, Benz A, Vorderstemann B, Webster JI, Schrenk D: Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression. Toxicology. 2002 Feb 28;171(2-3):137-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Hu XM, Hirano T, Oka K: Arsenic trioxide induces apoptosis equally in T lymphoblastoid leukemia MOLT-4 cells and P-gp-expressing daunorubicin-resistant MOLT-4 cells. Cancer Chemother Pharmacol. 2003 Feb;51(2):119-26. Epub 2002 Nov 20. [Article]
  2. Wei HL, Yao XJ, Li YN, Wang P, Zhao HS, Bai DC, Peng X, Ma LF: [Arsenic trioxide inhibits P-glycoprotein expression in multidrug-resistant human leukemia K562/ADM cell line that overexpresses mdr-1 gene and enhances their chemotherapeutic sensitivity]. Zhonghua Xue Ye Xue Za Zhi. 2003 Jan;24(1):28-31. [Article]
  3. Wei H, Su H, Bai D, Zhao H, Ge J, Wang B, Yao X, Ma L: Arsenic trioxide inhibits p-glycoprotein expression in multidrug-resistant human leukemia cells that overexpress the MDR1 gene. Chin Med J (Engl). 2003 Nov;116(11):1644-8. [Article]
  4. Kimura A, Ishida Y, Wada T, Yokoyama H, Mukaida N, Kondo T: MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice. Toxicol Appl Pharmacol. 2005 Feb 15;203(1):53-61. [Article]
  5. Cronin CJ, Mendel JE, Mukhtar S, Kim YM, Stirbl RC, Bruck J, Sternberg PW: An automated system for measuring parameters of nematode sinusoidal movement. BMC Genet. 2005 Feb 7;6:5. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48