Drug Information

Drug (ID: DG00112) and It's Reported Resistant Information
Name
Cytarabine
Synonyms
Alexan; AraC; Arabinocytidine; Arabinofuranosylcytosine; Arabinosylcytosine; Arabitin; Aracytidine; Aracytin; Aracytine; Arafcyt; Citarabina; Cytarabin; Cytarabina; Cytarabinoside; Cytarabinum; Cytarbel; Cytonal; Cytosar; Cytosinearabinoside; DepoCyte; Depocyt; Erpalfa; Iretin; Spongocytidine; Tarabine; Udicil; Arabinosyl Cytosine; Cytarabine liposome injection; Cytosine arabinofuranoside; Cytosine arabinose; Cytosine arabinoside; AR3; BTB15125; CHX 3311; U 19920A; Ara-C; Ara-Cytidine; Beta-Ara C; Beta-Arabinosylcytosine; Beta-cytosine arabinoside; Citarabina [INN-Spanish]; Cytarabinum [INN-Latin]; Cytosar-U; Cytosine arabinoside (VAN); Depocyt (TN); Depocyt (liposomal); Intrathecal (injected into the spinal fluid) DepoCyt; U-19920; Beta-D-Arabinosylcytosine; Cytosar-U (TN); Cytosine beta-D-arabinofuranoside; Cytosine beta-D-arabinofuranoside hydrochloride; Cytosine beta-D-arabinoside; Cytosine-beta-arabinoside; Intrathecal cytarabine (also known as ara-C); U-19,920; CYTARABINE (SEE ALSO CYTARABINE HYDROCHLORIDE 69-74-9); Cytarabine (JP15/USP/INN); Cytarabine [USAN:INN:BAN:JAN]; Cytosine 1-beta-D-arabinofuranoside; Cytosine, beta-D-arabinoside; Cytosine-beta-D-arabinofuranoside; Cytosine-1-beta-D-arabinofuranoside; Ara-C, Cytosine Arabinoside, Cytosar-U, Cytarabine; (beta-D-Arabinofuranosyl)cytosine; 1-.beta.-D-arabinofuranosyl-cytosine; 1-Arabinofuranosylcytosine; 1-beta-D-Arabinofaranosylcytosine; 1-beta-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-beta-D-Arabinofuranosylcytosine; 1-beta-D-Arabinofuranosylcytosine, Cytosine Arabinoside; 1-beta-D-Arabinosylcytosine; 1beta-Arabinofuranasylcytosine; 1beta-D-Arabinofuranosylcytosine; 1beta-D-Arabinosylcytosine; 2(1H)-Pyrimidinone, 4-amino-1-D-arabinofuranosyl-[CAS]; 4-Amino-1-arabinofuranosyl-2-oxo-1,2-dihydropyrimidin; 4-Amino-1-arabinofuranosyl-2-oxo-1,2-dihydropyrimidin [Czech]; 4-Amino-1-arabinofuranosyl-2-oxo-1,2-dihydropyrimidine; 4-Amino-1-b-D-arabinofuranosyl-2-(1H)-pyrimidinone; 4-Amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinon; 4-Amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinon [Czech]; 4-Amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinone; 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one; 4-amino-1-beta-D-arabinofuranosylpyrimidin-2(1H)-one
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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 Clinically Reported Resistance for This Drug (4 diseases)
Acute lymphocytic leukemia [ICD-11: 2B33]
[2]
Acute myeloid leukemia [ICD-11: 2A60]
[1]
Lymphoma [ICD-11: 2A90- 2A85]
[2]
Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Acute lymphocytic leukemia [ICD-11: 2B33]
[4]
Target Herpes simplex virus DNA polymerase UL30 (HSV UL30) DPOL_HHV11 [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C9H13N3O5
IsoSMILES
C1=CN(C(=O)N=C1N)[C@H]2[C@H]([C@@H]([C@H](O2)CO)O)O
InChI
1S/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1
InChIKey
UHDGCWIWMRVCDJ-CCXZUQQUSA-N
PubChem CID
6253
ChEBI ID
CHEBI:28680
TTD Drug ID
D07XSN
VARIDT ID
DR00416
INTEDE ID
DR0398
DrugBank ID
DB00987
Type(s) of Resistant Mechanism of This Drug
  DISM: Drug Inactivation by Structure Modification
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
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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-335 [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Nodal/TFG-alpha signaling pathway Regulation hsa04350
Wnt/alpha -catenin signaling pathway Regulation hsa04310
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 Relapse-free survival and overall survival assay
Mechanism Description The expression levels of miR-335 in bone marrow and serum samples from adult patients with AML (except M3) were significantly associated with the Ara-C-based chemotherapy response and clinical outcome after treatment.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-126-5p [5]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKTsignaling pathway Inhibition hsa04151
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
K562 cells Blood Homo sapiens (Human) CVCL_0004
HK-2 cells Kidney Homo sapiens (Human) CVCL_0302
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Transfection of the mimic miR-126-5p into the AML cell line, kG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.
Key Molecule: hsa-mir-181 [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Key Molecule: hsa-let-7a [7]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell growth Activation hsa05200
Cell invasion Activation hsa05200
Epithelial mesenchymal transition signaling pathway Activation hsa01521
In Vitro Model Molm13 cells Blood Homo sapiens (Human) CVCL_2119
OCI-AML3 cells Blood Homo sapiens (Human) CVCL_1844
In Vivo Model AML nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine.
Key Molecule: Bcl-2-like protein 11 (BCL2L11) [8]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Myeloid leukemia [ICD-11: 2A60.4]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description One of the predicted targets of miR-32 lies in the 3' untranslated region (UTR) of BCL2L11 gene, which encodes the pro-apoptotic protein Bim, miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis.
Key Molecule: hsa-mir-32 [8]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Myeloid leukemia [ICD-11: 2A60.4]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description One of the predicted targets of miR-32 lies in the 3' untranslated region (UTR) of BCL2L11 gene, which encodes the pro-apoptotic protein Bim, miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis.
Key Molecule: hsa-mir-21 [9]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description AMO-miR-21 significantly sensitizes HL60 cells to Ara-C byinducing apoptosis and these effects of AMO-miR-21 may be partially due to its up-regulation ofPDCD4.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Klotho (KL) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKTsignaling pathway Inhibition hsa04151
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
K562 cells Blood Homo sapiens (Human) CVCL_0004
HK-2 cells Kidney Homo sapiens (Human) CVCL_0302
Experiment for
Molecule Alteration		 RT-PCR; Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Transfection of the mimic miR-126-5p into the AML cell line, kG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.
Key Molecule: High mobility group protein B1 (HMGB1) [6]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
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		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [6]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
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		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Key Molecule: Programmed cell death protein 4 (PDCD4) [9]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description AMO-miR-21 significantly sensitizes HL60 cells to Ara-C byinducing apoptosis and these effects of AMO-miR-21 may be partially due to its up-regulation ofPDCD4.
Lymphoma [ICD-11: 2A90- 2A85]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytidine deaminase (CDA) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Also opposing the activation pathway are the two deaminase CDA and deoxycytidine monophosphate deaminase (dCMPD). Cytidine deaminase is a multi-subunit enzyme involved in the maintenance of the pyrimidine nucleotide pool within the cell and physiologically catalyzes the hydrolytic deamination of cytidine to uridine and deoxycytidine to deoxyuridine. In cytarabine biotransformation, CDA removes the amine group from its cytosine and converts the drug into the inactive uracil arabinoside derivative.
Key Molecule: Cardiolipin synthase (CLS) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description CMPD deaminates cytarabine-monophosphate to arabinosyl-uracil-monophosphate. A crucial role for this latter enzyme has been suggested in the metabolism of cytarabine-monophosphate in T-lymphoblastic leukemia.
Key Molecule: Deoxycytidine kinase (DCK) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Deoxycitidine kinase plays a pivotal role since phosphorylation of cytarabine preserves intracellular retention of the drug and prevents from inactivation to its uridine derivative, uracil arabinoside, by cytidine deaminase. The intracellular accumulation of cytarabine triphosphate, the active cytotoxic metabolite, is proportional to the cellular DCk level which has led to the conclusion that DCk enzyme retains a rate-limiting role for the activation of cytarabine.
Key Molecule: UMP-CMP kinase (CMPK1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.
Key Molecule: Nucleoside diphosphate kinase A (NME1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Since monophosphorilated intermediate of cytarabine activation is reduced by cytosolic 5'-nucleotidases NT5C2 and NT5C3, the activity level of this enzyme may represent one of the factors affecting the clinical outcome of cytarabine therapy. Increased expression of NT5C2 has been correlated with resistance to cytarabine chemotherapy and to a lower survival rate in a hundred patients undergoing cytarabine chemotherapy. An increase in the NT5C2 has emerged as a mechanism of resistance to cytarabine. Patients with AML and low expression level of NT5C2 have a better overall survival after treatment with cytarabine than patients with high expression. NT5C2 is implicated in pharmacokinetic of cytarabine has been associated with poor clinical outcome.
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family C10 (ABCC10) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.
Key Molecule: ATP-binding cassette sub-family C11(ABCC11) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.
Key Molecule: Solute carrier family 29 member 1 (SLC29A1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lymphoma [ICD-11: 2A90- 2A85]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Cytarabine gains entry into cells primarily as a false substrate through specialized nucleoside transporter proteins of SLC family, the human equilibrative nucleoside transportershENT1 and hENT2 (encoded by the gene SLC29A1 and SCL29A2, respectively) and the human concentrative nucleoside transporters hCNT3 (encoded by the gene SLC28A3). The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.
Acute lymphocytic leukemia [ICD-11: 2B33]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytidine deaminase (CDA) [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Jurkat cells Pleural effusion Homo sapiens (Human) CVCL_0065
Nalm-6 cells Peripheral blood Homo sapiens (Human) CVCL_0092
Experiment for
Molecule Alteration		 Real-time quantitative PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The results of real-time quantitative PCR showed that the expression of deoxycytidine kinase (DCk) and cytidine deaminase (CDA) were significantly down-regulated in drug-resistant cells (P<0.05).
Key Molecule: Deoxycytidine kinase (DCK) [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Jurkat cells Pleural effusion Homo sapiens (Human) CVCL_0065
Nalm-6 cells Peripheral blood Homo sapiens (Human) CVCL_0092
Experiment for
Molecule Alteration		 Real-time quantitative PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The results of real-time quantitative PCR showed that the expression of deoxycytidine kinase (DCk) and cytidine deaminase (CDA) were significantly down-regulated in drug-resistant cells (P<0.05).
Key Molecule: Cytidine deaminase (CDA) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Also opposing the activation pathway are the two deaminase CDA and deoxycytidine monophosphate deaminase (dCMPD). Cytidine deaminase is a multi-subunit enzyme involved in the maintenance of the pyrimidine nucleotide pool within the cell and physiologically catalyzes the hydrolytic deamination of cytidine to uridine and deoxycytidine to deoxyuridine. In cytarabine biotransformation, CDA removes the amine group from its cytosine and converts the drug into the inactive uracil arabinoside derivative.
Key Molecule: Cardiolipin synthase (CLS) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description CMPD deaminates cytarabine-monophosphate to arabinosyl-uracil-monophosphate. A crucial role for this latter enzyme has been suggested in the metabolism of cytarabine-monophosphate in T-lymphoblastic leukemia.
Key Molecule: Deoxycytidine kinase (DCK) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Deoxycitidine kinase plays a pivotal role since phosphorylation of cytarabine preserves intracellular retention of the drug and prevents from inactivation to its uridine derivative, uracil arabinoside, by cytidine deaminase. The intracellular accumulation of cytarabine triphosphate, the active cytotoxic metabolite, is proportional to the cellular DCk level which has led to the conclusion that DCk enzyme retains a rate-limiting role for the activation of cytarabine.
Key Molecule: UMP-CMP kinase (CMPK1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.
Key Molecule: Nucleoside diphosphate kinase A (NME1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Since monophosphorilated intermediate of cytarabine activation is reduced by cytosolic 5'-nucleotidases NT5C2 and NT5C3, the activity level of this enzyme may represent one of the factors affecting the clinical outcome of cytarabine therapy. Increased expression of NT5C2 has been correlated with resistance to cytarabine chemotherapy and to a lower survival rate in a hundred patients undergoing cytarabine chemotherapy. An increase in the NT5C2 has emerged as a mechanism of resistance to cytarabine. Patients with AML and low expression level of NT5C2 have a better overall survival after treatment with cytarabine than patients with high expression. NT5C2 is implicated in pharmacokinetic of cytarabine has been associated with poor clinical outcome.
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family C10 (ABCC10) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.
Key Molecule: ATP-binding cassette sub-family C11(ABCC11) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.
Key Molecule: Solute carrier family 29 member 1 (SLC29A1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Cytarabine gains entry into cells primarily as a false substrate through specialized nucleoside transporter proteins of SLC family, the human equilibrative nucleoside transportershENT1 and hENT2 (encoded by the gene SLC29A1 and SCL29A2, respectively) and the human concentrative nucleoside transporters hCNT3 (encoded by the gene SLC28A3). The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-181a [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
HL-60/Ara-C-resistant cells Blood Homo sapiens (Human) CVCL_1736
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Bcl-2 was conWrmed as adirect miR-181a target by immunoblot analysis andreporter gene assays. knockdown of Bcl-2 mimicked theeVect of enforced miR-181a expression by reducing cellviability. In addition, the apoptosis pathway was activated by cytochrome C release and caspase 9/caspase 3 activationafter miR-181a overexpression. Down-regulation of miR-181a and upregulation of Bcl-2in leukaemia cells confer resistance to Ara-C-based ther-apy.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [10]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Leukemia [ICD-11: 2B33.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
HL-60/Ara-C-resistant cells Blood Homo sapiens (Human) CVCL_1736
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Bcl-2 was conWrmed as adirect miR-181a target by immunoblot analysis andreporter gene assays. knockdown of Bcl-2 mimicked theeVect of enforced miR-181a expression by reducing cellviability. In addition, the apoptosis pathway was activated by cytochrome C release and caspase 9/caspase 3 activationafter miR-181a overexpression. Down-regulation of miR-181a and upregulation of Bcl-2in leukaemia cells confer resistance to Ara-C-based ther-apy.
References
Ref 1 Bone Marrow MicroRNA-335 Level Predicts the Chemotherapy Response and Prognosis of Adult Acute Myeloid Leukemia. Medicine (Baltimore). 2015 Aug;94(33):e0986. doi: 10.1097/MD.0000000000000986.
Ref 2 Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers. Cancers (Basel). 2021 Feb 25;13(5):966. doi: 10.3390/cancers13050966.
Ref 3 Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphomaCancer Biol Med. 2020 Aug 15;17(3):726-739. doi: 10.20892/j.issn.2095-3941.2020.0073.
Ref 4 [Establishment of Cytarabine-resistant Acute Lymphoblastic Leukemia Cell Lines and Its Resistance Mechanism]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021 Oct;29(5):1403-1410. doi: 10.19746/j.cnki.issn.1009-2137.2021.05.006.
Ref 5 Upregulation of microRNA-126-5p is associated with drug resistance to cytarabine and poor prognosis in AML patients. Oncol Rep. 2015 May;33(5):2176-82. doi: 10.3892/or.2015.3839. Epub 2015 Mar 6.
Ref 6 miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1. Int J Oncol. 2014 Jul;45(1):383-92. doi: 10.3892/ijo.2014.2390. Epub 2014 Apr 16.
Ref 7 CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J Clin Invest. 2013 Jun;123(6):2395-407. doi: 10.1172/JCI66553. Epub 2013 May 8.
Ref 8 MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res. 2011 Oct 1;71(19):6230-9. doi: 10.1158/0008-5472.CAN-11-1717. Epub 2011 Aug 4.
Ref 9 Anti-miR-21 oligonucleotide enhances chemosensitivity of leukemic HL60 cells to arabinosylcytosine by inducing apoptosis. Hematology. 2010 Aug;15(4):215-21. doi: 10.1179/102453310X12647083620840.
Ref 10 miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis. J Cancer Res Clin Oncol. 2012 Apr;138(4):595-602. doi: 10.1007/s00432-011-1137-3. Epub 2012 Jan 1.

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