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 Click to Show/Hide
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 (2 diseases) Acute lymphocytic leukemia [ICD-11: 2B33] [4] Acute myeloid leukemia [ICD-11: 2A60] [5]
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

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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Acute myeloid leukemia [ICD-11: 2A60]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[5]
Metabolic Type	Lipid metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myeloid leukemia
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.40E-07 Fold-change: 6.20E-01 Z-score: 6.08E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	TGF-beta signaling pathway		Activation	hsa04350
In Vitro Model	KG-1 A cells	Blood	Homo sapiens (Human)	CVCL_0374
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX9 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[5]
Metabolic Type	Lipid metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myeloid leukemia
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.40E-07 Fold-change: 6.20E-01 Z-score: 6.08E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	TGF-beta signaling pathway		Activation	hsa04350
In Vitro Model	K562/ADR cells	Blood	Homo sapiens (Human)	CVCL_0004
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX13 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[5]
Metabolic Type	Lipid metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myeloid leukemia
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.40E-07 Fold-change: 6.20E-01 Z-score: 6.08E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	TGF-beta signaling pathway		Activation	hsa04350
In Vitro Model	HL60/ADR cells	Blood	Homo sapiens (Human)	CVCL_0002
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX12 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[5]
Metabolic Type	Lipid metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myeloid leukemia
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.40E-07 Fold-change: 6.20E-01 Z-score: 6.08E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	TGF-beta signaling pathway		Activation	hsa04350
In Vitro Model	K562 cells	Blood	Homo sapiens (Human)	CVCL_0004
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX11 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[5]
Metabolic Type	Lipid metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myeloid leukemia
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.40E-07 Fold-change: 6.20E-01 Z-score: 6.08E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	TGF-beta signaling pathway		Activation	hsa04350
In Vitro Model	HL-60 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0002
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX10 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[5]
Metabolic Type	Lipid metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myeloid leukemia
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.40E-07 Fold-change: 6.20E-01 Z-score: 6.08E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	TGF-beta signaling pathway		Activation	hsa04350
In Vivo Model	HCC patients			Homo Sapiens
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Key Molecule: Cytochrome P450 family 1 subfamily A member 1 (CYP1A1)				[8]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cushing syndrome		Activation	hsa04934
In Vitro Model	SHI-1 cells	Bone marrow	Homo sapiens (Human)	CVCL_2191
	Skm1 cells	Blood	Homo sapiens (Human)	CVCL_0098
	U937 cells	Blood	Homo sapiens (Human)	CVCL_0007
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes.In vitroexperiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance.
Key Molecule: Cytochrome P450 family 1 subfamily B member 1 (CYP1B1)				[8]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cushing syndrome		Activation	hsa04934
In Vitro Model	SHI-1 cells	Bone marrow	Homo sapiens (Human)	CVCL_2191
	Skm1 cells	Blood	Homo sapiens (Human)	CVCL_0098
	U937 cells	Blood	Homo sapiens (Human)	CVCL_0007
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes.In vitroexperiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance.
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2)				[9]
Metabolic Type	Glucose metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Longevity regulating pathway - multiple species		Activation	hsa04213
In Vitro Model	AML cells	N.A.	Homo sapiens (Human)	N.A.
	HL-60 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0002
	IDH2 mutant AML cells	Blood	Homo sapiens (Human)	CVCL_S481
	KG-1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0374
Experiment for Drug Resistance	IC50 assay
Mechanism Description	The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells.
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2)				[9]
Metabolic Type	Glucose metabolism
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Longevity regulating pathway - multiple species		Activation	hsa04213
In Vivo Model	AML cell-transplanted tumor nude mice with IDH2 mutations			Mice
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells.
Key Molecule: Dihydrofolate reductase (DHFR)				[10]
Metabolic Type	Nucleic acid metabolism
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	THP1 cells	Pleural effusion	Homo sapiens (Human)	CVCL_0006
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.
Key Molecule: Squalene synthase (FDFT1)				[10]
Metabolic Type	Nucleic acid metabolism
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	THP1 cells	Pleural effusion	Homo sapiens (Human)	CVCL_0006
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-335				[1]
Resistant 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	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Nodal/TFG-alpha signaling pathway		Regulation	N.A.
	Wnt/alpha -catenin signaling pathway		Regulation	N.A.
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.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2)				[11]
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/Akt/mTOR signaling pathway		Regulation	N.A.
In Vitro Model	HL-60 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0002
	KG-1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0374
In Vivo Model	SPF-grade (BALB/C) nude mice model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR; Glycolysis metabolic enzyme assay; Flow cytometry; Western blot assay; Transcriptome sequencingc assay
Experiment for Drug Resistance	Cell proliferation assay; Drug sensitivity testing
Mechanism Description	OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2)				[11]
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K-Akt signaling pathway		Activation	hsa04151
In Vitro Model	HL-60 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0002
	KG-1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0374
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	The IDH2 mutations are involved in Ara-C resistance by affecting the process of glycolysis in AML, and the PI3K-Akt signaling pathway plays an important role in this process. These pathways are expected to be important targets for targeted therapeutic intervention in the AML setting.
Key Molecule: Acetyl-CoA acetyltransferase 2 (ACAT2)				[12]
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	DNA Damage Response Mechanism		Regulation	N.A.
In Vitro Model	MV-4-11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0064
	MOLM-13 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2119
	Kasumi-1 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0589
	TF-1 cells	Blood	Homo sapiens (Human)	CVCL_0559
Experiment for Molecule Alteration	RT-qPCR; Western blot assay
Experiment for Drug Resistance	MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description	DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients.
Key Molecule: Acetyl-CoA acetyltransferase 2 (ACAT2)				[12]
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	DNA Damage Response Mechanism		Regulation	N.A.
In Vitro Model	MV-4-11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0064
	MOLM-13 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2119
	Kasumi-1 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0589
	TF-1 cells	Blood	Homo sapiens (Human)	CVCL_0559
Experiment for Molecule Alteration	RT-qPCR; Western blot assay
Experiment for Drug Resistance	MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description	DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.
Key Molecule: Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)				[12]
Resistant Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	DNA Damage Response Mechanism		Regulation	N.A.
In Vitro Model	MV-4-11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0064
	MOLM-13 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2119
	Kasumi-1 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0589
	TF-1 cells	Blood	Homo sapiens (Human)	CVCL_0559
Experiment for Molecule Alteration	RT-qPCR; Western blot assay
Experiment for Drug Resistance	MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description	DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Programmed cell death protein 4 (PDCD4)				[6]
Sensitive Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myelocytic leukemia
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.63E-03 Fold-change: 7.01E-02 Z-score: 2.85E+00
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 blot 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.
Key Molecule: High mobility group protein B1 (HMGB1)				[7]
Sensitive Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease	Acute myelocytic leukemia
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.67E-02 Fold-change: -9.69E-03 Z-score: -2.10E+00
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: Klotho (KL)				[13]
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	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: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[7]
Sensitive Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			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 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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-126-5p				[13]
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	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				[7]
Sensitive Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			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 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				[14]
Sensitive Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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)				[15]
Sensitive Disease	Myeloid leukemia [ICD-11: 2A60.4]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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 blot 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				[15]
Sensitive Disease	Myeloid leukemia [ICD-11: 2A60.4]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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				[6]
Sensitive Disease	Acute myeloid leukemia [ICD-11: 2A60.0]			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
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.

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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Up-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Up-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Down-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Down-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Down-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Up-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Up-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Up-regulation	Molecule 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]
Resistant Disease	Lymphoma [ICD-11: 2A90- 2A85]		Disease Info
Molecule Alteration	Expression	Down-regulation	Molecule 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]
Resistant Disease	Acute lymphocytic leukemia [ICD-11: 2B33.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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]
Resistant Disease	Acute lymphocytic leukemia [ICD-11: 2B33.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule 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]
Resistant Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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				[16]
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
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)				[16]
Sensitive Disease	Leukemia [ICD-11: 2B33.6]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule 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 blot 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	The roles and mechanisms of TGFB1 in acute myeloid leukemia chemoresistance. Cell Signal. 2024 Apr;116:111027.
Ref 6	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 7	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 8	AHR signaling pathway mediates mitochondrial oxidative phosphorylation which leads to cytarabine resistance. Acta Biochim Biophys Sin (Shanghai). 2024 Apr 25;56(4):597-606.
Ref 9	Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
Ref 10	Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy. Comput Struct Biotechnol J. 2021 Jul 8;19:4059-4066.
Ref 11	Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
Ref 12	Silencing of the DNA damage repair regulator PPP1R15A sensitizes acute myeloid leukemia cells to chemotherapy. Ann Hematol. 2024 Aug;103(8):2853-2863.
Ref 13	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 14	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 15	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 16	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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Prof. Feng ZHU (zhufeng@zju.edu.cn)