Drug Information

Drug (ID: DG00266) and It's Reported Resistant Information

• Name: Bortezomib
• Synonyms: 179324-69-7; Velcade; Bortezomib (PS-341); UNII-69G8BD63PP; N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE; MLN-341; [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid; CHEMBL325041; 69G8BD63PP; Boronic acid,; DPBA; PROSCRIPT BORONIC ACID; LPD 341; LPD-341; VELCADE (TN); Velcade (TN); Pyz-Phe-boroLeu; Bortezomib(JAN/USAN/INN); Velcade, MG-341, PS-341, Bortezomib; N-[(1R)-1-(dihydroxyboranyl)-3-methylbutyl]-Nalpha-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide; Bortezomib (Proteasome inhibitor); Peptide boronate
• Indication:
  In total 3 Indication(s)
  Mature B-cell lymphoma [ICD-11: 2A85]; Approved; [1]
  Multiple myeloma [ICD-11: 2A83]; Approved; [1]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Cutaneous T-cell lymphoma [ICD-11: 2B00]; [2]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [3]
  Multiple myeloma [ICD-11: 2A83]; [4], [5]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Multiple myeloma [ICD-11: 2A83]; [6]
• Target: Cationic trypsinogen (PRSS1); TRY1_HUMAN; [1]
• Target: Kallikrein-related peptidase (KLK); NOUNIPROTAC; [1]
• Target: Proteasome (PS); NOUNIPROTAC; [1]
• Formula: C19H25BN4O4
• IsoSMILES: B([C@H](CC(C)C)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)C2=NC=CN=C2)(O)O
• InChI: 1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
• InChIKey: GXJABQQUPOEUTA-RDJZCZTQSA-N
• PubChem CID: 387447
• ChEBI ID: CHEBI:52717
• TTD Drug ID: D0SH3I
• VARIDT ID: DR01331
• INTEDE ID: DR0221
• DrugBank ID: DB00188

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  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 Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-29b-3p [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 8226 cells; Bone marrow; Homo sapiens (Human); CVCL_0014
• 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 Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via downregulating miR-29b-3p.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• 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: 8226 cells; Bone marrow; Homo sapiens (Human); CVCL_0014
• 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 Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p.

Key Molecule: Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• 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/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, leading to increase of G6PD expression and PPP flux, promoting cell proliferation and drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• 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: 8226 cells; Bone marrow; Homo sapiens (Human); CVCL_0014
• 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 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: LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via downregulating miR-29b-3p.

Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• 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/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, leading to increase of G6PD expression and PPP flux, promoting cell proliferation and drug resistance.

Key Molecule: Early growth response protein 1 (EGR1) [7]

• Molecule Alteration: Mutation; .
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exome sequencing assay; High-resolution copy-number array assay; Cytogenetics exome sequencing assay
• Mechanism Description: Knockdown of EGR1 in myeloma cells enhanced their resistance to bortezomib, and the clustered point mutation of key residues that we observed may have similar effects.

Key Molecule: Proteasome assembly chaperone 2 (PSMG2) [4], [5]

• Molecule Alteration: Missense mutation; p.E171K
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Key Molecule: Proteasome subunit beta type-5 (PSMB5) [5]

• Molecule Alteration: Mutation; .
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-324-5p [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• 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: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: ARH-77 cells; Peripheral blood; Homo sapiens (Human); CVCL_1072
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Colony formation assay
• Mechanism Description: Overexpression of miR324-5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. miR324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes. Down-regulation of miR324-5p is a novel mechanism of Hh signaling activation in MM.

Key Molecule: hsa-miR-631 [9]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR631/UbcH10/MDR1 signaling pathway; Regulation; hsa05206
• 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: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hsa-miR631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.

Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B) [10]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Activation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay; Annexin V-FLUOS assay
• Mechanism Description: miR202 contributes to sensitizing MM cells to drug significantly via activing JNk/SAPk signaling pathway. miR202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNk/SAPk signaling pathway.

Key Molecule: hsa-mir-202 [10]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Activation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay; Annexin V-FLUOS assay
• Mechanism Description: miR202 contributes to sensitizing MM cells to drug significantly via activing JNk/SAPk signaling pathway. miR202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNk/SAPk signaling pathway.

Key Molecule: hsa-mir-137 [11]

• 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: Epigenetic silencing of miR137 induces drug resistance and chromosomal instability by targeting AURkA in multiple myeloma.

Key Molecule: hsa-mir-497 [12]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.

Key Molecule: hsa-mir-202 [13]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin-conjugating enzyme E2 C (UBE2C) [9]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR631/UbcH10/MDR1 signaling pathway; Regulation; hsa05206
• 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: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hsa-miR631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.

Key Molecule: Aurora kinase A (AURKA) [11]

• 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: Epigenetic silencing of miR137 induces drug resistance and chromosomal instability by targeting AURkA in multiple myeloma.

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

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• 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 proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.

Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B) [13]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JNk/SAPk signaling pathway; Regulation; hsa05161
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST assay
• Mechanism Description: miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [3]

• Molecule Alteration: Mutation; .
• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to bortezomib in the waldenstrom macroglobulinemia.

Mature T-cell lymphoma [ICD-11: 2A90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [14]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Cutaneous T-cell lymphoma [ICD-11: 2B00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-125b-5p [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MyLa2000 cells; Skin; Homo sapiens (Human); CVCL_8328
• In Vitro Model: SeAx cells; Skin; Homo sapiens (Human); CVCL_5363
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. miR-125b-5p can regulates tumor growth in vivo,and increases cellular resistance to proteasome inhibitors via modulation of MAD4.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Max dimerization protein 4 (MXD4) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MyLa2000 cells; Skin; Homo sapiens (Human); CVCL_8328
• In Vitro Model: SeAx cells; Skin; Homo sapiens (Human); CVCL_5363
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. miR-125b-5p can regulates tumor growth in vivo,and increases cellular resistance to proteasome inhibitors via modulation of MAD4.

Osteosarcoma [ICD-11: 2B51]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-101 [15]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome maturation protein (POMP) [15]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Colon cancer [ICD-11: 2B90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-101 [15]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon carcinoma [ICD-11: 2B90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome maturation protein (POMP) [15]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon carcinoma [ICD-11: 2B90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-101 [15]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome maturation protein (POMP) [15]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Cervical cancer [ICD-11: 2C77]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-101 [15]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome maturation protein (POMP) [15]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

References

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