Drug Information

Drug (ID: DG00023) and It's Reported Resistant Information

• Name: Daunorubicin
• Synonyms: Daunorubicin; Daunomycin; 20830-81-3; Rubidomycin; Cerubidine; Daunorubicine; Acetyladriamycin; Leukaemomycin C; Daunorubicinum; Daunarubicinum; Daunorrubicina; Daunamycin; Cerubidin; DaunoXome; Rubomycin C; (+)-Daunomycin; Daunoblastin; Anthracyline; Rubomycin; Daunorubicinum [INN-Latin]; RP 13057; Daunorubicin [INN:BAN]; RCRA waste no U059; FI6339; NSC-82151; DAUNORUBICIN HCL; DaunoXome (TN); UNII-ZS7284E0ZP; CCRIS 914; ZS7284E0ZP; CHEBI:41977; HSDB 5095; C27H29NO10; NCI-C04693; EINECS 244-069-7; Ondena; NSC 83142; Acetyladriamycin; Daunoblastine; Antibiotics from Streptomyces coeruleorubidus; DM1; FI 6339; Dauno-Rubidomycine; Daunorubicin (INN); Daunorubicin (liposomal); Daunorubicin, Hydrochloride; VS-103; (1S,3S)-3-acetyl-3,5,12-trihydroxy-10-(methyloxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside; (1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranoside; (7S,9R)-9-Acetyl-7-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione; (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione; (8S-cis)-8-Acetyl-10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyrannosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-napthacenedione; (8S-cis)-8-Acetyl-10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione; Anthracycline
• Indication:
  In total 3 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved; [1]
  Kaposi sarcoma [ICD-11: 2B57]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Acute myeloid leukemia [ICD-11: 2A60]; [3]
  Pneumonia [ICD-11: CA40]; [4]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [5]
  Breast cancer [ICD-11: 2C60]; [6]
• Target: DNA replication (DNA repli); NOUNIPROTAC; [1]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [1]
• Formula: C27H29NO10
• IsoSMILES: C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C2C(=C4C(=C3O)C(=O)C5=C(C4=O)C(=CC=C5)OC)O)(C(=O)C)O)N)O
• InChI: 1S/C27H29NO10/c1-10-22(30)14(28)7-17(37-10)38-16-9-27(35,11(2)29)8-13-19(16)26(34)21-20(24(13)32)23(31)12-5-4-6-15(36-3)18(12)25(21)33/h4-6,10,14,16-17,22,30,32,34-35H,7-9,28H2,1-3H3/t10-,14-,16-,17-,22+,27-/m0/s1
• InChIKey: STQGQHZAVUOBTE-VGBVRHCVSA-N
• PubChem CID: 30323
• ChEBI ID: CHEBI:41977
• TTD Drug ID: D01XWG
• VARIDT ID: DR00284
• INTEDE ID: DR0424
• DrugBank ID: DB00694

Type(s) of Resistant Mechanism of This Drug

  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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [7]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CR1R12 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: NIH-G185 cells; Ovary; Homo sapiens (Human); CVCL_L991
• Experiment for Drug Resistance: propidium iodide staining assay
• Mechanism Description: In a NIH-G185 cell line presenting an overexpressed amount of the human transporter P-gp, cholesterol caused dramatic inhibition of daunorubicin transport with an IC(50) of about 8 microM yet had no effect on the parent cell line nor rhodamine 123 transport.

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: K562-R cells; Pleural effusion; Homo sapiens (Human); CVCL_5950
• In Vitro Model: NCI-H460/VBL cells; Bone marrow; Homo sapiens (Human); CVCL_0459
• In Vivo Model: SCID beige mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [3]

• Molecule Alteration: Missense mutation; p.R882H
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ADAM9/EGFR signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: DNMT3A mutations are most common in AML. DNMT3A mutant AML has been linked to anthracycline resistance and poor prognosis in some studies. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-33b [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MCL-1 participates in the regulation of DNR sensitivity mediated by miR-33b and overexpression of miR-33b enhances DNR sensitivity by downregulating MCL-1 in AML cells.

Key Molecule: hsa-mir-9 [9]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: miR-9 improved the anti-tumor effects of Dnr by inhibiting myeloid cell leukemia-1 (MCL-1) expression, which was dependent on downregulation of EIF5A2 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MCL-1 participates in the regulation of DNR sensitivity mediated by miR-33b and overexpression of miR-33b enhances DNR sensitivity by downregulating MCL-1 in AML cells.

Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-33b regulates sensitivity to daunorubicin in acute myelocytic leukemia by regulating eukaryotic translation initiation factor 5A-2.

Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [9]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: miR-9 improved the anti-tumor effects of Dnr by inhibiting myeloid cell leukemia-1 (MCL-1) expression, which was dependent on downregulation of EIF5A2 expression.

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125a [10]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRk2 and Puma which were proved to be direct targets of miR125a. Overexpression of miR125a induced drug resistance in HL-60, k562, and THP-1cell lines through reducing apoptosis.

Key Molecule: hsa-mir-125b [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR-125b downregulated GRk2 and PUMA, which inhibited apoptosis and induced leukemia cell resistance to DNR.

Key Molecule: hsa-mir-21 [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/DNR cells; Blood; Homo sapiens (Human); CVCL_4T87
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: DNR-induced drug resistance is associated with upregulation of miR-21 in the leukaemia cell line k562. miR-21 may regulate the survival of leukaemia cell lines by targeting PTEN expression and causing subsequent changes in the PI3k/Akt pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beta adrenoceptor kinase 1 (GRK2) [10]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRk2 and Puma which were proved to be direct targets of miR125a. Overexpression of miR125a induced drug resistance in HL-60, k562, and THP-1cell lines through reducing apoptosis.

Key Molecule: Bcl-2-binding component 3 (BBC3) [10]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRk2 and Puma which were proved to be direct targets of miR125a. Overexpression of miR125a induced drug resistance in HL-60, k562, and THP-1cell lines through reducing apoptosis.

Key Molecule: Beta adrenoceptor kinase 1 (GRK2) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR-125b downregulated GRk2 and PUMA, which inhibited apoptosis and induced leukemia cell resistance to DNR.

Key Molecule: Bcl-2-binding component 3 (BBC3) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR-125b downregulated GRk2 and PUMA, which inhibited apoptosis and induced leukemia cell resistance to DNR.

Key Molecule: Phosphatase and tensin homolog (PTEN) [5]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/DNR cells; Blood; Homo sapiens (Human); CVCL_4T87
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: DNR-induced drug resistance is associated with upregulation of miR-21 in the leukaemia cell line k562. miR-21 may regulate the survival of leukaemia cell lines by targeting PTEN expression and causing subsequent changes in the PI3k/Akt pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-210 [11]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: TEL/AML1+ Reh cells; Blood; Homo sapiens (Human); CVCL_ZV66
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: Functioning as a hypoxamir (i.e. a microRNA whose expression is upregulated by hypoxia), miR-210 targets many genes involved in a wide range of physiological processes, such as cell survival/proliferation, mitochondrial metabolism, protein modification/transport, DNA damage repair and angiogenesis. Increasing/decreasing miR-210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L-asparaginase and daunorubicin/dexamethasone/vincristine, respectively. miR-210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.

Key Molecule: hsa-mir-181a [12]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• 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
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Anti-apoptotic BCL-2 contributes to the survival and chemoresistance of quiescent leukemia CD34+ cells, leukemia cells with decreased miR-181a expression and elevated BCL-2 protein expression were more resistant to DNR than the control cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [12]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• 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
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Anti-apoptotic BCL-2 contributes to the survival and chemoresistance of quiescent leukemia CD34+ cells, leukemia cells with decreased miR-181a expression and elevated BCL-2 protein expression were more resistant to DNR than the control cells.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/AdrVp cells; Breast; Homo sapiens (Human); CVCL_4Y46
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Flow cytometric assay
• Mechanism Description: The mRNA encodes a 663-aa member of the ATP-binding cassette superfamily of transporters that we term breast cancer resistance protein (BCRP). Enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux of rhodamine 123 in the cloned transfected.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [13]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7/DX1 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: Sf9 cells; Ovary; Homo sapiens (Human); CVCL_0549
• In Vitro Model: HCMEC/D3 cells; Brain; Homo sapiens (Human); CVCL_U985
• Experiment for Drug Resistance: Flow Cytometry assay
• Mechanism Description: QT2C2Me2 (8) inhibited P-gp transport of R123, calcein-AM, doxorubicin, BODIPY-FL-verapamil, and [3H]-daunorubicin similarly to QT2C2 (1), with IC50 values in the low micromolar range. These IC50 values were 13- to 75-fold lower than those for the QT monomer. These results indicated that both dimers are effective P-gp inhibitor.

Kidney cancer [ICD-11: 2C90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [14]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Flp-In-293/Mock cells; Kidney; Homo sapiens (Human); CVCL_U421
• In Vitro Model: Flp-In-293/ABCB1 cells; Kidney; Homo sapiens (Human); CVCL_U421
• Experiment for Molecule Alteration: ATPase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Through calcein assays, we found that epimagnolin A inhibited the ABCB1-mediated export of calcein. This result suggests that epimagnolin A behaved as inhibitor or substrate for ABCB1. In ATPase assays, epimagnolin A stimulated ABCB1-dependent ATPase activity. This result indicates that epimagnolin A was recognised as a substrate by ABCB1, since ABCB1 utilises energy derived from ATP hydrolysis for substrate transport. Furthermore, in MTT assays we found that the cytotoxicity of daunorubicin, doxorubicin, vinblastine, and vincristine was enhanced by epimagnolin A in a manner comparable to verapamil, a typical substrate for ABCB1.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MATE family efflux transporter (ABEM) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

References

• Ref 1: MicroRNA-33b regulates sensitivity to daunorubicin in acute myelocytic leukemia by regulating eukaryotic translation initiation factor 5A-2. J Cell Biochem. 2020 Jan;121(1):385-393. doi: 10.1002/jcb.29192. Epub 2019 Jun 21.
• Ref 2: microRNA 125b promotes leukemia cell resistance to daunorubicin by inhibiting apoptosis. Mol Med Rep. 2014 May;9(5):1909-16. doi: 10.3892/mmr.2014.2011. Epub 2014 Mar 6.
• Ref 3: The role of mutations in epigenetic regulators in myeloid malignancies. Immunol Rev. 2015 Jan;263(1):22-35. doi: 10.1111/imr.12246.
• Ref 4: AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob Agents Chemother. 2005 Oct;49(10):4362-4. doi: 10.1128/AAC.49.10.4362-4364.2005.
• Ref 5: Involvement of miR-21 in resistance to daunorubicin by regulating PTEN expression in the leukaemia K562 cell line. FEBS Lett. 2011 Jan 21;585(2):402-8. doi: 10.1016/j.febslet.2010.12.027. Epub 2010 Dec 25.
• Ref 6: A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15665-70. doi: 10.1073/pnas.95.26.15665.
• Ref 7: Cholesterol interaction with the daunorubicin binding site of P-glycoprotein. Biochem Biophys Res Commun. 2000 Oct 5;276(3):909-16. doi: 10.1006/bbrc.2000.3554.
• Ref 8: HG-829 is a potent noncompetitive inhibitor of the ATP-binding cassette multidrug resistance transporter ABCB1. Cancer Res. 2012 Aug 15;72(16):4204-13. doi: 10.1158/0008-5472.CAN-12-0743. Epub 2012 Jul 3.
• Ref 9: miR-9 Enhances the Chemosensitivity of AML Cells to Daunorubicin by Targeting the EIF5A2/MCL-1 Axis. Int J Biol Sci. 2019 Jan 1;15(3):579-586. doi: 10.7150/ijbs.29775. eCollection 2019.
• Ref 10: Involvement of miR-125a in resistance to daunorubicin by inhibiting apoptosis in leukemia cell lines. Tumour Biol. 2017 Apr;39(4):1010428317695964. doi: 10.1177/1010428317695964.
• Ref 11: Effect of microRNA-210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer Sci. 2014 Apr;105(4):463-72. doi: 10.1111/cas.12370. Epub 2014 Mar 30.
• Ref 12: miR-181a sensitizes a multidrug-resistant leukemia cell line K562/A02 to daunorubicin by targeting BCL-2. Acta Biochim Biophys Sin (Shanghai). 2012 Mar;44(3):269-77. doi: 10.1093/abbs/gmr128. Epub 2012 Jan 26.
• Ref 13: Reversible dimers of the atypical antipsychotic quetiapine inhibit p-glycoprotein-mediated efflux in vitro with increased binding affinity and in situ at the blood-brain barrier. ACS Chem Neurosci. 2014 Apr 16;5(4):305-17. doi: 10.1021/cn4002329. Epub 2014 Feb 7.
• Ref 14: Epimagnolin A, a tetrahydrofurofuranoid lignan from Magnolia fargesii, reverses ABCB1-mediated drug resistance .Phytomedicine. 2018 Dec 1;51:112-119. doi: 10.1016/j.phymed.2018.06.030. Epub 2018 Jun 20. 10.1016/j.phymed.2018.06.030