Drug Information

Drug (ID: DG00254) and It's Reported Resistant Information

• Name: Mitoxantrone
• Synonyms: DHAD; DHAQ; Dihydroxyanthraquinone; MIX; Misostol; Mitoxanthrone; Mitoxantron; Mitoxantrona; Mitoxantronum; Mitozantrone; DHAQ HCl; Mitoxantrone [INN]; Mitozantrone hydrochloride; Mitoxantrone 2HCl; Liposome Encapsulated Mitoxantrone (LEM); Misostol (TN); Mitoxantrona [INN-Spanish]; Mitoxantrone (INN); Mitoxantrone (free base); Mitoxantronum [INN-Latin]; Novantrone (TN); AN-584/42007670; Novantrone(R) (mitoxantrone for injection concentrate); DHAQ (*Diacetate salt*); MITOXANTRONE, Mitoxantrone Hydrochloride, Mitoxantrone dihydrochloride, MITOXANTHRONE HYDROCHLORIDE; MITOXANTRONE, 1,4-DIHYDROXY-5,8-BIS({2-[(2-HYDROXYETHYL)AMINO]ETHYL}AMINO)ANTHRA-9,10-QUINONE; 1,4-Bis(2-(2-hydroxyethylamino)ethyl)amino)-5,8-dihydroxyanthraquinone; 1,4-DIHYDROXY-5,8-BIS({2-[(2-HYDROXYETHYL)AMINO]ETHYL}AMINO)-9,10-ANTHRACENEDIONE; 1,4-Dihydroxy-5,8-bis(2-((2-hydroxyethyl)amino)ethylamino)-9,10-anthracenedione; 1,4-Dihydroxy-5,8-bis(5-hydroxy-3-azapentylamino)anthrachinon; 1,4-Dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione; 1,4-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione; 1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthra-9,10-quinone; 1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthracene-9,10-dione; 5,8-Bis((2-((2-hydroxyethyl)amino)ethyl)amino)-1,4-dihydroxyanthraquinone; 9,10-Anthracenedione, 1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-(9CI)
• Indication:
  In total 2 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Phase 1/2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Keloid/hypertrophic scars [ICD-11: EE60]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Breast cancer [ICD-11: 2C60]; [3]
  Prostate cancer [ICD-11: 2C82]; [4]
• Target: DNA topoisomerase II (TOP2); TOP2A_HUMAN TOP2B_HUMAN; [1]
• Formula: C22H28N4O6
• IsoSMILES: C1=CC(=C2C(=C1NCCNCCO)C(=O)C3=C(C=CC(=C3C2=O)O)O)NCCNCCO
• InChI: 1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2
• InChIKey: KKZJGLLVHKMTCM-UHFFFAOYSA-N
• PubChem CID: 4212
• ChEBI ID: CHEBI:50729
• TTD Drug ID: D0R3JB
• VARIDT ID: DR00269
• INTEDE ID: DR1102
• DrugBank ID: DB01204

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

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 G2 (ABCG2) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.C592A
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cytotoxicity assay
• Mechanism Description: Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.C592A+p.C603A
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cytotoxicity assay
• Mechanism Description: Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.C603A+p.C608A
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cytotoxicity assay
• Mechanism Description: Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.C608A
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cytotoxicity assay
• Mechanism Description: Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.

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

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.K86M
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colorimetric cytotoxicity assy assay
• Mechanism Description: Cells expressing ABCG2-wt or ABCG2-wt-MYC showed increased resistance to mitoxantrone as reflected in a sevenfold increase in IC50 value as compared to that observed for non-transfected cells (0.36 uM and 0.29 uM, for ABCG2-wt or ABCG2-wt-MYC expressing cells compared to 0.05 uM in non-transfected cells). ABCG2-k86M and ABCG2-k86M-HA displayed sensitivity comparable to that of non-transfected cells consistent with loss of function with IC50 values for mitoxantrone of 0.047 uM and and 0.043 uM

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [7]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/BCRP cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/MDR cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Drug Resistance: Growth inhibition assay
• Mechanism Description: Some flavonoids have BCRP-inhibitory activity. 3',4',7-trimethoxyflavone showed the strongest anti-BCRP activity with RI50 values of 0.012 uM for SN-38 and 0.044 uM for mitoxantrone. 3',4',7-trimethoxyflavone and acacetin, showed only low anti-P-gp activity, with the remainder displaying no suppressive effects against P-gp. None of the flavonoids that we tested inhibite.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-494 [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: KG1a cells; Pleural effusion; Homo sapiens (Human); CVCL_1824
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-494 activation suppresses bone marrow stromal cell-mediated drug resistance in acute myeloid leukemia cells.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [8]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-181a down-regulated BCRP expression, and sensitized MX-resistant MCF-7/MX cells to MX.

Key Molecule: hsa-mir-328 [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• 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/MX100 cells; Breast; Homo sapiens (Human); CVCL_LB54
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Sulforhodamine B assay
• Mechanism Description: miR-328 targets ABCG2 3'-UTR and, consequently, controls ABCG2 protein expression and influences drug disposition in human breast cancer cells. miR-328-directed down-regulation of ABCG2 expression in MCF-7/MX100 cells resulted in an increased mitoxantrone sensitivity.

Key Molecule: hsa-miR-101-3p [9]

• Resistant Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: Sk-BR-7 cells; Breast; Homo sapiens (Human); CVCL_5218
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: SUM44PE cells; Breast; Homo sapiens (Human); CVCL_3424
• In Vitro Model: SUM52PE cells; Breast; Homo sapiens (Human); CVCL_3425
• Experiment for Molecule Alteration: Microarray analyses
• Mechanism Description: This gene is up-regulated in mitoxantrone-resistance cells

Key Molecule: hsa-miR-522-3p [9]

• Resistant Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: Sk-BR-7 cells; Breast; Homo sapiens (Human); CVCL_5218
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: SUM44PE cells; Breast; Homo sapiens (Human); CVCL_3424
• In Vitro Model: SUM52PE cells; Breast; Homo sapiens (Human); CVCL_3425
• Experiment for Molecule Alteration: Microarray analyses
• Mechanism Description: This gene is up-regulated in mitoxantrone-resistance cells

Key Molecule: hsa-miR-640 [9]

• Resistant Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: Sk-BR-7 cells; Breast; Homo sapiens (Human); CVCL_5218
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: SUM44PE cells; Breast; Homo sapiens (Human); CVCL_3424
• In Vitro Model: SUM52PE cells; Breast; Homo sapiens (Human); CVCL_3425
• Experiment for Molecule Alteration: Microarray analyses
• Mechanism Description: This gene is up-regulated in mitoxantrone-resistance cells

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [8]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-181a down-regulated BCRP expression, and sensitized MX-resistant MCF-7/MX cells to MX.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [8]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-181a down-regulated BCRP expression, and sensitized MX-resistant MCF-7/MX cells to MX.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• 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/MX100 cells; Breast; Homo sapiens (Human); CVCL_LB54
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Sulforhodamine B assay
• Mechanism Description: miR-328 targets ABCG2 3'-UTR and, consequently, controls ABCG2 protein expression and influences drug disposition in human breast cancer cells. miR-328-directed down-regulation of ABCG2 expression in MCF-7/MX100 cells resulted in an increased mitoxantrone sensitivity.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [10]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• 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
• In Vitro Model: MCF-7/AdrVpPR cells; Breast; Homo sapiens (Human); CVCL_4Y46
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Flow cytometric assay
• Mechanism Description: The overexpression of BCRP mRNA in MCF-7/AdrVp cells, which is diminished in MCF-7/AdrVpPR, suggests an important role for BCRP in resistance to cytotoxic agents. Furthermore, the enforced overexpression of BCRP in MCF-7 cells diminished daunorubicin cellular accumulation and imparted a pattern of drug crossresistance to the transfected cells that was virtually identical to that of MCF-7/AdrVp.

Drug Sensitive Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-519c [11]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BCRP/ABCG2; Regulation; N.A.
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry analysis
• Mechanism Description: Our data suggest that miR-519c and -328 have greater impact on ABCG2 expression than miR-520h in MCF-7 human breast cancer cells, and the presence of proximal miR-519c MRE explains the action of miR-519c on shortened ABCG2 3'UTR.

Key Molecule: hsa-miR-181a-2 [12]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c athymic nude mice (female, 4-6 weeks old and 16-20 g); Mus musculus
• Experiment for Molecule Alteration: miRNA microarray analysis; Luciferase activity assay; qRT-PCR; Western blot
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: MiR-181a was found to be the most significantly down-regulated miRNA in MCF-7/MX cells. Luciferase activity assay showed that miR-181a mimics inhibited BCRP expression by targeting the 3' untranslated region (UTR) of the BCRP mRNA. Overexpression of miR-181a down-regulated BCRP expression, and sensitized MX-resistant MCF-7/MX cells to MX.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-302a [13]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer.

Key Molecule: hsa-mir-302b [13]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer.

Key Molecule: hsa-mir-302c [13]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer.

Key Molecule: hsa-mir-302d [13]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer.

Key Molecule: hsa-mir-487a [14]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell survival; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ectopic miR-487a down-regulated BCRP expression at the mRNA and protein levels, increasing the intracellular accumulation and cytotoxicity of Mitoxantrone in resistant MCF-7/MX breast cancer cells.

Key Molecule: hsa-miR-125b-1-3p [9]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: Sk-BR-7 cells; Breast; Homo sapiens (Human); CVCL_5218
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: SUM44PE cells; Breast; Homo sapiens (Human); CVCL_3424
• In Vitro Model: SUM52PE cells; Breast; Homo sapiens (Human); CVCL_3425
• Experiment for Molecule Alteration: Microarray analyses
• Mechanism Description: This gene is up-regulated in mitoxantrone-sensitive cells

Key Molecule: hsa-miR-497-3p [9]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT-20 cells; Mammary gland; Homo sapiens (Human); CVCL_0178
• In Vitro Model: BT-474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: BT-549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: SK-BR-3 cells; Pleural effusion; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: EVSA-T cells; Ascites; Homo sapiens (Human); CVCL_1207
• In Vitro Model: Sk-BR-7 cells; Breast; Homo sapiens (Human); CVCL_5218
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: SUM44PE cells; Breast; Homo sapiens (Human); CVCL_3424
• In Vitro Model: SUM52PE cells; Breast; Homo sapiens (Human); CVCL_3425
• Experiment for Molecule Alteration: Microarray analyses
• Mechanism Description: This gene is up-regulated in mitoxantrone-sensitive cells

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [13]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [14]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ectopic miR-487a down-regulated BCRP expression at the mRNA and protein levels, increasing the intracellular accumulation and cytotoxicity of Mitoxantrone in resistant MCF-7/MX breast cancer cells.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [14]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell survival; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ectopic miR-487a down-regulated BCRP expression at the mRNA and protein levels, increasing the intracellular accumulation and cytotoxicity of Mitoxantrone in resistant MCF-7/MX breast cancer cells.

Prostate cancer [ICD-11: 2C82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [4]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Fluorescence microscopy test apoptosis assay
• Mechanism Description: Transient expression of GAS5 enhances apoptosis and decreases the survival of 22Rv1 cells, forced variation of GAS5 gene expression can modulate cellular responses to various apoptotic stimuli, including a range of chemotherapeutic drugs.

ICD-14: Skin diseases

Keloid/hypertrophic scars [ICD-11: EE60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Resistant Disease: Keloid [ICD-11: EE60.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• In Vitro Model: Keloid fibroblasts; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: MDR-1-positive keloid cells exhibited roundness as opposed to the usual spindle shape. Contrarily, MDR-1-positive cells in normal skin remained spindle shaped. Such a phenomenon suggests that MDR-1 positive keloid cells represent a subpopulation important in keloid pathogenesis. MDR-1 (also known as ABCB1 or P-glycoprotein) is one of the best characterized membrane transporters.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Resistant Disease: Keloid [ICD-11: EE60.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• In Vitro Model: Keloid fibroblasts; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: MDR-1-positive keloid cells exhibited roundness as opposed to the usual spindle shape. Contrarily, MDR-1-positive cells in normal skin remained spindle shaped. Such a phenomenon suggests that MDR-1 positive keloid cells represent a subpopulation important in keloid pathogenesis. MDR-1 (also known as ABCB1 or P-glycoprotein) is one of the best characterized membrane transporters.

References

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