Drug Information

Drug (ID: DG00154) and It's Reported Resistant Information

• Name: Epirubicin
• Synonyms: Ellence; Epiadriamycin; Epidoxorubicin; Epirubicina; Epirubicine; Epirubicinum; Pidorubicin; Pidorubicina; Pidorubicine; Pidorubicinum; Ridorubicin; Epirubicina [Spanish]; Epirubicine [French]; Epirubicinum [Latin]; Pharmorubicin Pfs; IMI 28; WP 697; Ebewe (TN); Ellence (TN); Epi-DX; Epirubicin (INN); Epirubicin (TN); Epirubicin [INN:BAN]; Epirubicina [INN-Spanish]; Epirubicine [INN-French]; Epirubicinum [INN-Latin]; Farmorubicin (TN); Pharmorubicin (TN); Pidorubicina [INN-Spanish]; Pidorubicine [INN-French]; Pidorubicinum [INN-Latin]; (1S,3S)-3,5,12-trihydroxy-3-(hydroxyacetyl)-10-(methyloxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-arabino-hexopyranoside; (1S,3S)-3,5,12-trihydroxy-3-(hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-arabino-hexopyranoside; (7S,9R)-7-[(2S,4S,5R,6S)-4-Amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione; (7S,9S)-7-[(2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione; 10-((3-amino-2,3,6-trideoxy-beta-L-arabino-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-(8S-cis)-5,12-naphthacenedione; 4'-Epi-DXR; 4'-Epiadriamycin; 4'-epi-DX; 4'-epi-Doxorubicin; 4'-epidoxorubicin; 4-Epidoxorubicin
• Indication:
  In total 1 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Breast cancer [ICD-11: 2C60]; [2]
  Lung cancer [ICD-11: 2C25]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
  Bladder cancer [ICD-11: 2C94]; [4]
  Breast cancer [ICD-11: 2C60]; [5]
  Sarcoma [ICD-11: 2C35]; [6]
• Target: DNA topoisomerase II (TOP2); TOP2A_HUMAN TOP2B_HUMAN; [1]
• Formula: C27H29NO11
• 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)CO)O)N)O
• InChI: 1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22-,27-/m0/s1
• InChIKey: AOJJSUZBOXZQNB-VTZDEGQISA-N
• PubChem CID: 41867
• ChEBI ID: CHEBI:47898
• TTD Drug ID: D0C9XJ
• VARIDT ID: DR00170
• INTEDE ID: DR0591
• DrugBank ID: DB00445

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

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Multiple myeloma [ICD-11: 2A83]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-137 [7]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic expression of miR137 strongly reduced the expression of AURkA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21, overexpression of miR137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and RNA damage pathways.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aurora kinase A (AURKA) [7]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: MM1S cells; Peripheral blood; Homo sapiens (Human); CVCL_8792
• In Vitro Model: OPM-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic expression of miR137 strongly reduced the expression of AURkA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21, overexpression of miR137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and RNA damage pathways.

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27b [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-G1 (CCNG1) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-4443 [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Activation; hsa04030
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-4443 promotes the resistance of non-small cell lung cancer cells to epirubicin by downregulating INPP4A and regulating the activation of JAk2/STAT3 pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Inositol polyphosphate-4-phosphatase type I A (INPP4A) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Activation; hsa04030
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-4443 promotes the resistance of non-small cell lung cancer cells to epirubicin by downregulating INPP4A and regulating the activation of JAk2/STAT3 pathway.

Sarcoma [ICD-11: 2C35]

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: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Key Molecule: Myc proto-oncogene protein (MYC) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Key Molecule: Transcription factor SOX-2 (SOX2) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Key Molecule: Catenin beta interacting protein 1 (CTNNBIP1) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

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-129-5p [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• 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: CCK8 toxicity assay
• Mechanism Description: NONHSAT101069 was upregulated in BC tissues and promoted epirubicin resistance, migration and invasion of BC cells via regulation of NONHSAT101069/miR-129-5p/Twist1 axis, highlighting its potential as an oncogene and a therapeutic biomarker for BC.

Key Molecule: Long non-protein coding RNA (NONHSAT101069) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SUM1315 cells; Breast; Homo sapiens (Human); CVCL_5589
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR,Northern blot
• Experiment for Drug Resistance: CCK8 toxicity assay
• Mechanism Description: Twist1 is a target protein of miR-129-5p and positively regulates by NONHSAT101069 in BC cells. and it stimulates epirubicin resistance, migration, invasion, and EMT progression of BC cells.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cullin4A/MDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Quantitative real-time RT-PCR
• Experiment for Drug Resistance: CellTiter AQueous One Solution Cell Proliferation Assay
• Mechanism Description: LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway. H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 LncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel.

Key Molecule: Bcl-2-interacting killer (BIK) [5]

• Molecule Alteration: Expression; Down-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: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF-7R cells; Breast; Homo sapiens (Human); CVCL_Y493
• In Vitro Model: ZR-75-1R cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V apoptosis assay; Fow cytometry analysis
• Mechanism Description: LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIk and NOXA.

Key Molecule: Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) [5]

• Molecule Alteration: Expression; Down-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: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF-7R cells; Breast; Homo sapiens (Human); CVCL_Y493
• In Vitro Model: ZR-75-1R cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V apoptosis assay; Fow cytometry analysis
• Mechanism Description: LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIk and NOXA.

Key Molecule: hsa-let-7a [10]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Lower let-7a expression was associated with epirubicin resistance in primary breast tumors. Moreover, upregulation of let-7a expression sensitized resistant breast tumor cell lines to epirubicin by enhancing cellular apoptosis in vitro. Collectively, these findings indicate that lower expression of let-7a miRNA can induce chemoresistance in breast cancer by enhancing cellular apoptosis and suggest that let-7a may be used as a therapeutic target to modulate epirubicin-based chemotherapy resistance.

Key Molecule: hsa-mir-204 [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Low miR-024 expression was enhancing chemotherapeutic resistance of breast cancer patients.

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

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• 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: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT20 cells; Breast; Homo sapiens (Human); CVCL_0178
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: E2F3, and in some settings E2F1, induce apoptosis through p53-dependent or -independent pathways, Overexpression of miR-125b in MCF-7 cells significantly down-regulated E2F3 protein level, overexpression of miR-125b caused a marked inhibition of anticancer drug activity and increased resistance in breast cancer cells in vitro.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Cyclin-G2 (CCNG2) [12]

• Molecule Alteration: Expression; Down-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: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Exosomal microRNA miR1246 promotes cell proliferation, invasion and drug resistance by suppressing the expression level of CCNG2 in Breast Cancer.

Key Molecule: hsa-miR-1246 [12]

• 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: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Exosomal microRNA miR1246 promotes cell proliferation, invasion and drug resistance by suppressing the expression level of CCNG2 in Breast Cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Twist-related protein 1 (TWST1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SUM1315 cells; Breast; Homo sapiens (Human); CVCL_5589
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 toxicity assay
• Mechanism Description: Twist1 is a target protein of miR-129-5p and positively regulates by NONHSAT101069 in BC cells. and it stimulates epirubicin resistance, migration, invasion, and EMT progression of BC cells.

Key Molecule: Transcription factor E2F3 (E2F3) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• 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: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT20 cells; Breast; Homo sapiens (Human); CVCL_0178
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: E2F3, and in some settings E2F1, induce apoptosis through p53-dependent or -independent pathways, Overexpression of miR-125b in MCF-7 cells significantly down-regulated E2F3 protein level, overexpression of miR-125b caused a marked inhibition of anticancer drug activity and increased resistance in breast cancer cells in vitro.

Key Molecule: Fanconi anemia group D2 protein (FANCD2) [13]

• Molecule Alteration: Missense mutation; p.G56V
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Kidney cancer [ICD-11: 2C90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27b [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-G1 (CCNG1) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Bladder cancer [ICD-11: 2C94]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34b-3p [14]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: hsa-miR-22-3p [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [4]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [15]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.

Key Molecule: hsa-miR-193a-3p [16]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Lymphoid enhancer-binding factor 1 (LEF1) [15]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.

Key Molecule: Transcription factor 7 (TCF7) [15]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.

Key Molecule: Presenilin-1 (PSEN1) [16]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

References

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