Drug Information

Drug (ID: DG00108) and It's Reported Resistant Information
Name
Arsenic trioxide
Synonyms
Arsenox; Arsentrioxide; Naonobin; Trisenox; Trixenox; Acide arsenieux [French]; Anhydride arsenieux [French]; Arseni trioxydum; Arsenic blanc [French]; Arsenic trioxide [JAN]; Arsenigen saure [German]; Arsenious Acid Anhydride; Arsenious trioxide; Arsenous oxide [ISO]; Oxyde Arsenieux; Arsenic trioxide [UN1561] [Poison]; Arsenic oxide (As2O3); Arsenic(III) trioxide; Oxyde Arsenieux [ISO-French]; Trisenox (TN); Arsenic trioxide (JP15/USAN); Arsenic(3+)
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Indication
In total 1 Indication(s)
Mature B-cell lymphoma [ICD-11: 2A85]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
Acute myeloid leukemia [ICD-11: 2A60]
[2]
Acute lymphocytic leukemia [ICD-11: 2B33]
[3]
Lung cancer [ICD-11: 2C25]
[4]
Target Inhibitor of nuclear factor kappa-B kinase beta (IKKB) IKKB_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
As2O3
IsoSMILES
[O-2].[O-2].[O-2].[As+3].[As+3]
InChI
1S/2As.3O/q2*+3;3*-2
InChIKey
QTLQKAJBUDWPIB-UHFFFAOYSA-N
PubChem CID
14888
TTD Drug ID
D07VIK
VARIDT ID
DR00119
DrugBank ID
DB01169
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  MRAP: Metabolic Reprogramming via Altered Pathways
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
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Lung cancer [ICD-11: 2C25]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Quinone reductase 1 (NQO1) [4]
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung cancer
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 6.02E-66
Fold-change: 2.58E-01
Z-score: 2.01E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Nrf2 signaling pathway Activation hsa05208
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 MTT Assay
Mechanism Description miR155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. miR155 mediated ATO resistance by upregulating the Nrf2 signaling pathway, but downregulating cellular apoptosis in lung cancer cells.
Key Molecule: Heme oxygenase 1 (HMOX1) [4]
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Nrf2 signaling pathway Activation hsa05208
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 MTT Assay
Mechanism Description miR155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. miR155 mediated ATO resistance by upregulating the Nrf2 signaling pathway, but downregulating cellular apoptosis in lung cancer cells.
Key Molecule: NFE2-related factor 2 (NRF2) [4]
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Nrf2 signaling pathway Activation hsa05208
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 MTT Assay
Mechanism Description miR155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. miR155 mediated ATO resistance by upregulating the Nrf2 signaling pathway, but downregulating cellular apoptosis in lung cancer cells.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-155 [4]
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Nrf2 signaling pathway Activation hsa05208
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT Assay
Mechanism Description miR155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. miR155 mediated ATO resistance by upregulating the Nrf2 signaling pathway, but downregulating cellular apoptosis in lung cancer cells.
Chronic myeloid leukemia [ICD-11: 2A20]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-21 [5]
Sensitive Disease Chronic myelogenous leukemia [ICD-11: 2A20.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell growth Inhibition hsa05200
In Vitro Model K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-21 post-transcriptionally down-regulates tumor suppressor PDCD4. AMO-miR-21 sensitized leukemic k562 cells to ATO by inducing apoptosis partially due to its up-regulation of PDCD4 protein level.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Programmed cell death protein 4 (PDCD4) [5]
Sensitive Disease Chronic myelogenous leukemia [ICD-11: 2A20.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell growth Inhibition hsa05200
In Vitro Model K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-21 post-transcriptionally down-regulates tumor suppressor PDCD4. AMO-miR-21 sensitized leukemic k562 cells to ATO by inducing apoptosis partially due to its up-regulation of PDCD4 protein level.
Acute myeloid leukemia [ICD-11: 2A60]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: NFE2-related factor 2 (NRF2) [6]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Oxidative stress response signaling pathway Regulation N.A.
In Vitro Model MV4-11 ATO-R C4 cells N.A. Homo sapiens (Human) N.A.
MV4-11 ATO-R C6 cells N.A. Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Apoptosis analysis; Intracellular ROS assay; Flow cytometry assay
Mechanism Description We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.
Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [2]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.
Key Molecule: B-cell lymphoma 2 (BCL2) [2]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.
Key Molecule: Nucleolar protein 3 (NOL3) [2]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.
Key Molecule: Interleukin-10 (IL10) [2]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.
Key Molecule: CD70 antigen (CD70) [2]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.
Key Molecule: Baculoviral IAP repeat-containing protein 3 (BIRC3) [2]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Amplification
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-204 [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cancer progression Inhibition hsa05200
In Vitro Model AML-5 cells Peripheral blood Homo sapiens (Human) CVCL_1620
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Transglutaminase 2 (TG2) [7]
Metabolic Type Redox metabolism
Sensitive Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF7 cells Breast Homo sapiens (Human) CVCL_0031
NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Baculoviral IAP repeat-containing protein 6 (BIRC6) [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation BIRC6/p53-mediated apoptosis signaling pathway Activation hsa04210
In Vitro Model AML-5 cells Peripheral blood Homo sapiens (Human) CVCL_1620
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis.
Acute lymphocytic leukemia [ICD-11: 2B33]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-21 [3]
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description PDCD4 has been reported to be involved in growth, apoptosis, invasion and cell cycle etc. AMO-miR-21 significantly sensitizes HL60 and k562 cells to ATO by inducing apoptosis, and these effects of AMO-miR-21 may be partially due to its up-regulation of PDCD4.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Programmed cell death protein 4 (PDCD4) [3]
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description PDCD4 has been reported to be involved in growth, apoptosis, invasion and cell cycle etc. AMO-miR-21 significantly sensitizes HL60 and k562 cells to ATO by inducing apoptosis, and these effects of AMO-miR-21 may be partially due to its up-regulation of PDCD4.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-153 [8]
Sensitive Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Forced expression of miR-153 only in k562 cells has no significant effects on cell growth and apoptosis. However, when cells were additionally treated with As2O3, significant greater apoptosis was observed in the miR-153 overexpressed group.
Liver cancer [ICD-11: 2C12]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-539 [9]
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
Skhep1 cells Liver Homo sapiens (Human) CVCL_0525
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay; Flow cytometry assay
Mechanism Description microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma.
References
Ref 1 MicroRNA-204 Potentiates the Sensitivity of Acute Myeloid Leukemia Cells to Arsenic Trioxide. Oncol Res. 2019 Sep 23;27(9):1035-1042. doi: 10.3727/096504019X15528367532612. Epub 2019 Apr 8.
Ref 2 Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors. Pharmaceuticals (Basel). 2024 Nov 14;17(11):1529.
Ref 3 miRNA-21 regulates arsenic-induced anti-leukemia activity in myelogenous cell lines. Med Oncol. 2011 Mar;28(1):211-8. doi: 10.1007/s12032-009-9413-7. Epub 2010 Feb 9.
Ref 4 miR-155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. Sci Rep. 2017 Sep 22;7(1):12155. doi: 10.1038/s41598-017-06061-x.
Ref 5 Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis. Cancer Sci. 2010 Apr;101(4):948-54. doi: 10.1111/j.1349-7006.2010.01489.x. Epub 2010 Jan 7.
Ref 6 Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia. Ann Hematol. 2024 Jun;103(6):1919-1929.
Ref 7 ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2. Int J Mol Sci. 2023 Jun 30;24(13):10938.
Ref 8 miR-153 sensitized the K562 cells to As2O3-induced apoptosis. Med Oncol. 2012 Mar;29(1):243-7. doi: 10.1007/s12032-010-9807-6. Epub 2011 Jan 26.
Ref 9 microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma. Life Sci. 2016 Dec 1;166:34-40. doi: 10.1016/j.lfs.2016.10.002. Epub 2016 Oct 4.

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