Identification

Name
Arsenic trioxide
Accession Number
DB01169  (APRD00171)
Type
Small Molecule
Groups
Approved, Investigational
Description

Arsenic trioxide is a chemotheraputic 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. Due to the toxic nature of arsenic, this drug carries significant health risks. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide.

Structure
Thumb
Synonyms
  • Acide Arsenieux
  • Anhydride Arsenieux
  • Arsenic Blanc
  • Arsenic oxide
  • Arsenic(III) oxide
  • arsénico trióxido
  • Arsenigen Saure
  • Arsenolite
  • Arsenous oxide
  • Arsenous oxide anhydride
  • Diarsenic oxide
  • Diarsenic trioxide
  • White arsenic
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TrisenoxSolution10 mgIntravenousTeva2013-09-09Not applicableCanada
TrisenoxInjection, solution1 mg/1mLIntravenousCephalon, Inc.2000-10-152021-08-15Us
TrisenoxInjection, solution2 mg/1mLIntravenousCephalon2017-12-22Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Arsenic TrioxideInjection, solution1 mg/1mLIntravenousFresenius Kabi USA, LLC2018-08-31Not applicableUs
Arsenic TrioxideInjection1 mg/1mLIntravenousIngenus Pharmaceuticals, LLC2018-11-15Not applicableUs
Arsenic TrioxideInjection, solution1 mg/1mLIntravenousAmring Pharmaceuticals Inc.2018-11-14Not applicableUs
Categories
UNII
S7V92P67HO
CAS number
1327-53-3
Weight
Average: 197.84
Monoisotopic: 197.827934
Chemical Formula
As2O3
InChI Key
IKWTVSLWAPBBKU-UHFFFAOYSA-N
InChI
InChI=1S/As2O3/c3-1-5-2-4
IUPAC Name
diarsorosooxidane
SMILES
O=[As]O[As]=O

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

Associated Conditions
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
Human
AThioredoxin reductase 1, cytoplasmic
inhibitor
Human
ATranscription factor AP-1
inducer
Human
AG1/S-specific cyclin-D1
antagonist
Human
AMitogen-activated protein kinase 3
inducer
Human
AMitogen-activated protein kinase 1
inducer
Human
URAC-alpha serine/threonine-protein kinase
inducer
Human
UCyclin-dependent kinase inhibitor 1Not AvailableHuman
UHistone deacetylase 1Not AvailableHuman
UProtein PMLNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

75% bound

Metabolism

The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases. The main site of methylation reactions appears to be the liver. Arsenic is stored mainly in liver, kidney, heart, lung, hair and nails.

Route of elimination

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

Half life
Not Available
Clearance
Not Available
Toxicity

Symptoms of overdose include convulsions, muscle weakness and confusion.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Arsenic trioxide.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Arsenic trioxide.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Arsenic trioxide is combined with 2-Methoxyethanol.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Arsenic trioxide.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Arsenic trioxide.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Arsenic trioxide.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Arsenic trioxide.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Arsenic trioxide.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Arsenic trioxide is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbacavirAbacavir may decrease the excretion rate of Arsenic trioxide which could result in a higher serum level.
Food Interactions
Not Available

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. [PubMed:17640917]
External Links
KEGG Drug
D02106
PubChem Compound
261004
PubChem Substance
46506448
ChemSpider
229103
ChEMBL
CHEMBL1200978
Therapeutic Targets Database
DNC000255
PharmGKB
PA448486
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Arsenic_trioxide
ATC Codes
L01XX27 — Arsenic trioxide
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (46.3 KB)
MSDS
Download (78.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentAgnogenic Myeloid Metaplasia1
1CompletedTreatmentAdult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma1
1CompletedTreatmentBrain Cancer1
1CompletedTreatmentBrain and Central Nervous System Tumors2
1CompletedTreatmentColorectal Cancers1
1CompletedTreatmentLeukemias1
1CompletedTreatmentLeukemias / Malignant Lymphomas1
1CompletedTreatmentLeukemias / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm1
1CompletedTreatmentMultiple Myeloma and Plasma Cell Neoplasm1
1CompletedTreatmentMyelodysplastic Syndromes and Leukemia, Myeloid, Acute1
1CompletedTreatmentRefractory Multiple Myeloma / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific / Unspecified Childhood Solid Tumor, Protocol Specific1
1RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1TerminatedTreatmentAcute Promyelocytic Leukemia (APL)1
1TerminatedTreatmentEssential Thrombocythemia (ET) / Polycythemia Vera (PV) / Primary Myelofibrosis1
1TerminatedTreatmentLeukemias / Myelodysplastic Syndromes1
1TerminatedTreatmentChronic Chronic myelogenous leukemia1
1WithdrawnTreatmentMultiple Myeloma and Plasma Cell Neoplasm1
1, 2Active Not RecruitingTreatmentBrain and Central Nervous System Tumors1
1, 2CompletedBasic ScienceBasal Cell Carcinoma of the Skin / Recurrent Skin Cancer1
1, 2CompletedTreatmentLeukemias3
1, 2CompletedTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Diseases1
1, 2CompletedTreatmentMultiple Myeloma (MM) / Transplantation, Stem Cell1
1, 2CompletedTreatmentMultiple Myeloma and Plasma Cell Neoplasm1
1, 2CompletedTreatmentMyelodysplastic Syndrome1
1, 2CompletedTreatmentPlasma Cell Myeloma1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2TerminatedTreatmentLeukemias / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes1
1, 2TerminatedTreatmentMetastatic Melanoma1
2Active Not RecruitingTreatmentAcute Promyelocytic Leukemia (APL)1
2Active Not RecruitingTreatmentLeukemias1
2CompletedTreatmentAcute Promyelocytic Leukemia (APL)1
2CompletedTreatmentBrain and Central Nervous System Tumors / Cancer of the Ovary / Childhood Germ Cell Tumor / Extragonadal Germ Cell Tumor / Liver Cancer / Neuroblastomas / Renal Cancers / Retinoblastoma / Sarcomas1
2CompletedTreatmentCancer Other Than Leukemia1
2CompletedTreatmentCarcinoma, Small Cell / Lung Cancers / Lung neoplasm malignant / Pulmonary Cancer / Pulmonary Neoplasms1
2CompletedTreatmentCervical Cancers1
2CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
2CompletedTreatmentChronic Myeloproliferative Disorders / Leukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Diseases1
2CompletedTreatmentExtragonadal Germ Cell Tumor / Testicular germ cell tumour1
2CompletedTreatmentLeukemia Acute Myeloid Leukemia (AML)1
2CompletedTreatmentLeukemia, Other / Malignancies1
2CompletedTreatmentLeukemias6
2CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
2CompletedTreatmentLiver Cancer1
2CompletedTreatmentLung Cancers1
2CompletedTreatmentMalignant Lymphomas1
2CompletedTreatmentMalignant Neoplasm of Pancreas1
2CompletedTreatmentMultiple Myeloma (MM)2
2CompletedTreatmentProstate Cancer1
2CompletedTreatmentRecurrent Transitional Cell Cancer of the Renal Pelvis and Ureter / Recurrent Urethral Cancer / Transitional Cell Carcinoma of the Bladder / Ureteral Cancer1
2CompletedTreatmentRenal Cancers1
2Not Yet RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / P53 Mutation1
2Not Yet RecruitingTreatmentPrimary Hepatocellular Carcinoma1
2RecruitingTreatmentAcute Promyelocytic Leukemia (APL)1
2RecruitingTreatmentAcute Promyelocytic Leukemia With PML-RARA / Leukemias1
2RecruitingTreatmentChronic Graft Versus Host Disease / Immune System Diseases1
2RecruitingTreatmentChronic Myelomonocytic Leukemia / Leukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome1
2RecruitingTreatmentNeuroblastomas1
2TerminatedNot AvailableMyelodysplastic Syndromes (MDS)1
2TerminatedTreatmentAcute Myelogenous Leukaemia (AML)1
2TerminatedTreatmentAdenocarcinoma of the Esophagus / Stage III Esophageal Cancer / Stage IV Esophageal Cancer1
2TerminatedTreatmentEndometrial Carcinoma1
2TerminatedTreatmentHepatocellular,Carcinoma1
2TerminatedTreatmentLeukemias2
2TerminatedTreatmentLeukemias / Myelodysplastic Syndromes1
2TerminatedTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms1
2TerminatedTreatmentMalignant Lymphomas1
2TerminatedTreatmentMultiple Myeloma and Plasma Cell Neoplasm1
2TerminatedTreatmentMyelodysplastic Syndrome1
2TerminatedTreatmentSystemic Lupus1
2Unknown StatusTreatmentLeukemias / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes1
2Unknown StatusTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms1
2Unknown StatusTreatmentMultiple Myeloma and Plasma Cell Neoplasm2
2WithdrawnTreatmentAcute Promyelocytic Leukemia (APL)1
2WithdrawnTreatmentAdult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Minimally Differentiated Myeloid Leukemia (M0) / Adult Acute Monoblastic Leukemia (M5a) / Adult Acute Monocytic Leukemia (M5b) / Adult Acute Myeloblastic Leukemia With Maturation (M2) / Adult Acute Myeloblastic Leukemia Without Maturation (M1) / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Adult Acute Myelomonocytic Leukemia (M4) / Adult Erythroleukemia (M6a) / Adult Pure Erythroid Leukemia (M6b) / Recurrent Adult Acute Myeloid Leukemia1
2WithdrawnTreatmentCancer, Breast1
2WithdrawnTreatmentLeukemias2
2WithdrawnTreatmentRefractory Plasma Cell Neoplasm / Stage I Multiple Myeloma / Stage II Multiple Myeloma / Stage III Multiple Myeloma1
2WithdrawnTreatmentRefractory Plasma Cell Neoplasm / Stage II Multiple Myeloma / Stage III Multiple Myeloma1
2, 3CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
2, 3Unknown StatusTreatmentHepatocellular,Carcinoma1
3Active Not RecruitingTreatmentChildhood Acute Promyelocytic Leukemia (M3) / Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies1
3Active Not RecruitingTreatmentLeukemias1
3CompletedTreatmentAdult Acute Myeloid Leukemia With T(15;17)(q22;q12) / Adult Acute Promyelocytic Leukemia (M3) / Childhood Acute Promyelocytic Leukemia (M3) / Untreated Adult Acute Myeloid Leukemia / Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies1
3Not Yet RecruitingTreatmentMyelodysplastic Syndromes / P53 Mutation1
3RecruitingTreatmentAcute Promyelocytic Leukemia (APL)2
3RecruitingTreatmentAcute Promyelocytic Leukemia With PML-RARA / Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA / Childhood Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA / Untreated Adult Acute Myeloid Leukemia / Untreated Childhood Myeloid Neoplasm1
3TerminatedTreatmentLeukemia Acute Myeloid Leukemia (AML)1
4CompletedTreatmentAcute Promyelocytic Leukemia (APL)1
4RecruitingTreatmentChildhood Acute Promyelocytic Leukemia1
4Unknown StatusTreatmentRefractory Acute Promyelocytic Leukemia / Relapsed Acute Promyelocytic Leukemia1
Not AvailableNot Yet RecruitingTreatmentSkin Basal Cell Carcinoma1
Not AvailableTerminatedTreatmentChronic Lymphocytic Leukemia (CLL) - Refractory / Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue / Leukemia, Prolymphocytic / Nodal marginal zone B-cell lymphomas / Recurrent Adult Diffuse Small Cleaved Cell Lymphoma / Recurrent Grade 1 Follicular Lymphoma / Recurrent Grade 2 Follicular Lymphoma / Recurrent Marginal Zone Lymphoma / Recurrent Small Lymphocytic Lymphoma / Splenic Marginal Zone Lymphoma / Waldenström's Macroglobulinemia (WM)1

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
Injection, solutionIntravenous1 mg/1mL
Injection, solutionIntravenous2 mg/1mL
SolutionIntravenous10 mg
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)
US6723351No2004-04-202018-11-10Us
US6855339No2005-02-152018-11-10Us
US6861076No2005-03-012018-11-10Us
US6884439No2005-04-262018-11-10Us
US6982096No2006-01-032018-11-10Us
US8273379No2012-09-252018-11-10Us

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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Metalloid oxide / Inorganic oxide / Inorganic metalloid salt / Inorganic arsenic compound
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:16230390]
  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. [PubMed:16387740]
  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. [PubMed:17450217]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
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. [PubMed:17640917]
Kind
Protein
Organism
Human
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. [PubMed:12075113]
  2. Dong Z: The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect. 2002 Oct;110 Suppl 5:757-9. [PubMed:12426127]
  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. [PubMed:12475910]
  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. [PubMed:12547826]
  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. [PubMed:12637567]
Kind
Protein
Organism
Human
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. [PubMed:12480548]
  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. [PubMed:16230390]
  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. [PubMed:16387740]
  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. [PubMed:17005224]
  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. [PubMed:17370311]
Kind
Protein
Organism
Human
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. [PubMed:12472888]
  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. [PubMed:14516795]
  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. [PubMed:14674888]
  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. [PubMed:15849723]
  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. [PubMed:17158527]
Kind
Protein
Organism
Human
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. [PubMed:12426127]
  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. [PubMed:12529330]
Kind
Protein
Organism
Human
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. [PubMed:12472888]
  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. [PubMed:12529330]
  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. [PubMed:15580309]
  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. [PubMed:15916724]
  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. [PubMed:16239170]
Kind
Protein
Organism
Human
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. [PubMed:20074581]
Kind
Protein
Organism
Human
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. [PubMed:20074581]
Kind
Protein
Organism
Human
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. [PubMed:20378816]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d 24-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 oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP1B1
Uniprot ID
Q16678
Uniprot Name
Cytochrome P450 1B1
Molecular Weight
60845.33 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
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. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. 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. [PubMed:15833926]

Carriers

Kind
Protein
Organism
Human
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. [PubMed:25863441]

Transporters

Kind
Protein
Organism
Human
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. [PubMed:11836020]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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. [PubMed:12647012]
  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. [PubMed:12679007]
  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. [PubMed:14642128]
  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. [PubMed:15694464]
  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. [PubMed:15698479]

Drug created on June 13, 2005 07:24 / Updated on November 20, 2018 13:19