Drug Information

Drug (ID: DG00267) and It's Reported Resistant Information
Name
Methotrexate
Synonyms
Methotrexate; 1959/5/2; Rheumatrex; Amethopterin; Metatrexan; Hdmtx; Abitrexate; Mexate; Methylaminopterinum; Methotrexatum; Antifolan; Metotrexato; Methylaminopterin; MTX; (S)-2-(4-(((2,4-Diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)pentanedioic acid; Methotrexat; Amethopterine; Maxtrex; Rasuvo; L-Amethopterin; A-Methopterin; A-Methpterin; Amethopterin L-; Folex-Pfs; Methotrexat-Ebewe; N-Bismethylpteroylglutamic acid; Methotrexate, L-; Metotressato [DCIT]; Methotextrate; Mexate-Aq; [3H]methotrexate
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Indication
In total 5 Indication(s)
Leukaemia [ICD-11: 2A60-2B33]
Approved
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Phase 3
[1]
Vitreoretinopathy [ICD-11: 9B78]
Phase 3
[1]
Rheumatoid arthritis [ICD-11: FA20]
Phase 1
[1]
Prostate cancer [ICD-11: 2C82]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (8 diseases)
Acute lymphocytic leukemia [ICD-11: 2B33]
[2]
Colon cancer [ICD-11: 2B90]
[3]
Colorectal cancer [ICD-11: 2B91]
[4]
Gestational trophoblastic neoplasia [ICD-11: 2C75]
[5]
Lupus erythematosus [ICD-11: 4A40]
[6]
Osteosarcoma [ICD-11: 2B51]
[3]
Psoriasis [ICD-11: EA90]
[7]
Rheumatoid arthritis [ICD-11: FA20]
[8]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (4 diseases)
Brain cancer [ICD-11: 2A00]
[9]
Colon cancer [ICD-11: 2B90]
[10]
Colorectal cancer [ICD-11: 2B91]
[11]
Osteosarcoma [ICD-11: 2B51]
[12]
Target Proton-coupled folate transporter (SLC46A1) PCFT_HUMAN [1]
Solute carrier family 19 member 1 (SLC19A1) S19A1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C20H22N8O5
IsoSMILES
CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
InChI
1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
InChIKey
FBOZXECLQNJBKD-ZDUSSCGKSA-N
PubChem CID
126941
ChEBI ID
CHEBI:44185
TTD Drug ID
D0SV8E
VARIDT ID
DR00082
INTEDE ID
DR1045
DrugBank ID
DB00563
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Brain cancer [ICD-11: 2A00]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [9]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Ependymoma [ICD-11: 2A00.05]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell invasion Activation hsa05200
In Vitro Model BXD-1425EPN cells Embryo Homo sapiens (Human) CVCL_Y105
EPN1 cells Embryo Homo sapiens (Human) N.A.
EPN7 cells Embryo Homo sapiens (Human) N.A.
EPN7R cells Embryo Homo sapiens (Human) N.A.
DKFZ-EP1 cells Embryo Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [9]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Ependymoma [ICD-11: 2A00.05]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell invasion Activation hsa05200
In Vitro Model BXD-1425EPN cells Embryo Homo sapiens (Human) CVCL_Y105
EPN1 cells Embryo Homo sapiens (Human) N.A.
EPN7 cells Embryo Homo sapiens (Human) N.A.
EPN7R cells Embryo Homo sapiens (Human) N.A.
DKFZ-EP1 cells Embryo Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).
Key Molecule: Multidrug resistance protein 1 (ABCB1) [9]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Ependymoma [ICD-11: 2A00.05]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell invasion Activation hsa05200
In Vitro Model BXD-1425EPN cells Embryo Homo sapiens (Human) CVCL_Y105
EPN1 cells Embryo Homo sapiens (Human) N.A.
EPN7 cells Embryo Homo sapiens (Human) N.A.
EPN7R cells Embryo Homo sapiens (Human) N.A.
DKFZ-EP1 cells Embryo Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).
Acute lymphocytic leukemia [ICD-11: 2B33]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.
Key Molecule: Hematopoietic SH2 domain containing (HSH2D) [13]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HuT-78 cells Peripheral blood Homo sapiens (Human) CVCL_0337
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The expression of HSH2D was downregulated in T-ALL compared with B-cell ALL. Western blotting and reverse transcription-quantitative PCR demonstrated that the overexpression of HSH2 resulted in the inhibition of CD28-mediated IL-2 activation. In related experiments with drug-resistant cell lines, it was determined that HSH2D expression is necessary for HuT-78 cells to be resistant to MTX.
Osteosarcoma [ICD-11: 2B51]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Lung cancer associated transcript 1 (LUCAT1) [14]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
LUCAT1/miR200c/ABCB1 pathway Regulation hsa05206
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
HOS cells Bone Homo sapiens (Human) CVCL_0312
HFOB cells Bone Homo sapiens (Human) CVCL_3708
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CCK8 assay; Transwell invasion assay
Mechanism Description The modulation of LUCAT1 on ABCB1 through sponging miR200c. LncRNA LUCAT1 knockdown suppress the expression levels drug resistance related genes, proliferation, invasion and tumor growth of osteosarcoma cells in vitro and vivo, hence, LUCAT1 upregulation leads to improved chemoresistance.
Key Molecule: hsa-mir-200c [14]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
LUCAT1/miR200c/ABCB1 pathway Regulation hsa05206
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
HOS cells Bone Homo sapiens (Human) CVCL_0312
HFOB cells Bone Homo sapiens (Human) CVCL_3708
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Transwell invasion assay
Mechanism Description Long non-coding RNA LUCAT1 modulates methotrexate resistance in osteosarcoma via miR200c/ABCB1 axis.
Key Molecule: hsa-mir-375 [15]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Multivariate analysis of overall survival or disease-free survival assay
Mechanism Description miR375 overexpression could increase the cisplatin sensitivity of human gastric cancer cells by regulating ERBB2.
Key Molecule: Delta-like protein 1 (DLL1) [16]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ATF2/ATF3/ATF4 signaling pathway Inhibition hsa04915
In Vitro Model G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 IC50 assay; Flow cytometric analysis
Mechanism Description miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.
Key Molecule: hsa-miR-34a-5p [16]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ATF2/ATF3/ATF4 signaling pathway Inhibition hsa04915
In Vitro Model G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 IC50 assay; Flow cytometric analysis
Mechanism Description miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.
Key Molecule: hsa-miR-34a-5p [17]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Key Molecule: hsa-miR-146b-5p [12]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Wnt/Beta-catenin signaling pathway Regulation hsa04310
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
hFOB1.19 cells Fetal bone Homo sapiens (Human) CVCL_3708
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.
Key Molecule: hsa-mir-215 [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
p53 signaling pathway Activation hsa04115
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [14]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell colony Activation hsa05200
Cell senescence Inhibition hsa04218
Cell viability Activation hsa05200
LUCAT1/miR200c/ABCB1 pathway Regulation hsa05206
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
HOS cells Bone Homo sapiens (Human) CVCL_0312
HFOB cells Bone Homo sapiens (Human) CVCL_3708
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Luciferase reporter assay
Experiment for
Drug Resistance		 CCK8 assay; Transwell invasion assay
Mechanism Description LncRNA LUCAT1 and ABCB1 protein were both up-regulated in MG63/MTX and HOS/MTX cells when treated with methotrexate. ABCB1, acting as a vital protein of drug resistance, participated in the multiple drug resistance occurrence.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [17]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Key Molecule: E3 ubiquitin-protein ligase ZNRF3 (ZNRF3) [12]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Wnt/Beta-catenin signaling pathway Regulation hsa04310
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
hFOB1.19 cells Fetal bone Homo sapiens (Human) CVCL_3708
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.
Key Molecule: Dihydrofolate reductase (DHFR) [3]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
p53 signaling pathway Activation hsa04115
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 Western blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.
Key Molecule: Thymidylate synthase (TYMS) [3]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
p53 signaling pathway Activation hsa04115
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 Western blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-29a [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-29a suppressed MTX resistance and promoted cell apoptosis by downregulating MCL1 expression.
Key Molecule: hsa-mir-29b [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-29b suppressed MTX resistance and promoted cell apoptosis by downregulating MCL1 expression.
Key Molecule: hsa-mir-29c [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-29c suppressed MTX resistance and promoted cell apoptosis by downregulating MCL1 expression.
Key Molecule: hsa-mir-382 [18]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: hsa-mir-140 [19]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Collagen alpha-1(III) chain (COL3A1) [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-29a suppressed MTX resistance and promoted cell apoptosis by downregulating COL3A1 expression.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Overexpression of miR-29a suppressed MTX resistance and promoted cell apoptosis by downregulating MCL1 expression.
Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3) [18]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: Krueppel-like factor 12 (KLF12) [18]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.
Key Molecule: Histone deacetylase 4 (HDAC4) [19]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
Experiment for
Molecule Alteration		 Western blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.
Colon cancer [ICD-11: 2B90]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-224 [10]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.
Key Molecule: hsa-mir-215 [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
p53 signaling pathway Activation hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Solute carrier family 4 member 4 (SLC4A4) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Phosphatidate cytidylyltransferase 2 (CDS2) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.
Key Molecule: m7GpppN-mRNA hydrolase (DCP2) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.
Key Molecule: Galectin-related protein (GRP) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.
Key Molecule: Histone acetyltransferase KAT6A (KAT6A) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.
Key Molecule: Dihydrofolate reductase (DHFR) [3]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
p53 signaling pathway Activation hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 Western blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.
Key Molecule: Thymidylate synthase (TYMS) [3]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
p53 signaling pathway Activation hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 Western blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-140 [19]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
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		 WST-1 assay
Mechanism Description miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Histone deacetylase 4 (HDAC4) [19]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 Western blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 WST-1 assay
Mechanism Description miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.
Colorectal cancer [ICD-11: 2B91]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Taurine up-regulated 1 (TUG1) [4]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT-8 cells Colon Homo sapiens (Human) CVCL_2478
HT-29-R cells Colon Homo sapiens (Human) CVCL_6834
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description TUG1 mediates methotrexate resistance in colorectal cancer via miR186/CPEB2 axis.
Key Molecule: H19, imprinted maternally expressed transcript (H19) [11]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Wnt/Beta-catenin signaling pathway Activation hsa04310
In Vitro Model HT-29 cells Colon Homo sapiens (Human) CVCL_0320
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/beta-catenin pathway.
Key Molecule: hsa-mir-505 [20]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell viability Activation hsa05200
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
SW620 cells Colon Homo sapiens (Human) CVCL_0547
LS174T cells Colon Homo sapiens (Human) CVCL_1384
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony-forming assay; Transwell assay; Wound healing assay; Flow cytometry assay
Mechanism Description miR-505 advanced MTX-induced LS174T cells migration and invasiveness as well as depressed LS174T/MTX cell apoptosis through the down-regulation of RASSF8.
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Solute carrier family 46 member 1 (SLC46A1) [21]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Ussing chamber system assay
Mechanism Description Cefadroxil and methotrexate (each 10 uM) were selected as substrates to evaluate the functions of the uptake transport mediated by PEPT1 and PCFT, respectively. Gly-Sar (20 mM) and folate (200 uM), typical substrates of PEPT1 and PCFT, respectively, were used to saturate the functions of PEPT1 and PCFT. The mucosal-to-serosal transport and mucosal uptake of cefadroxil and methotrexate were significantly decreased in the presence of PEPT1/PCFT inhibitor cocktail in all batches of tissue sections.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cytoplasmic polyadenylation element-binding protein 2 (CPEB2) [4]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT-8 cells Colon Homo sapiens (Human) CVCL_2478
HT-29-R cells Colon Homo sapiens (Human) CVCL_6834
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description CPEB2 is the functional target of miR186 to modulate colorectal cancer cells sensitive to MTX.
Key Molecule: Ras association domain-containing protein 8 (RASSF8) [20]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Cell viability Activation hsa05200
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
SW620 cells Colon Homo sapiens (Human) CVCL_0547
LS174T cells Colon Homo sapiens (Human) CVCL_1384
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Colony-forming assay; Transwell assay; Wound healing assay; Flow cytometry assay
Mechanism Description miR-505 advanced MTX-induced LS174T cells migration and invasiveness as well as depressed LS174T/MTX cell apoptosis through the down-regulation of RASSF8.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-186 [4]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT-8 cells Colon Homo sapiens (Human) CVCL_2478
HT-29-R cells Colon Homo sapiens (Human) CVCL_6834
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description TUG1 mediates methotrexate resistance in colorectal cancer via miR186/CPEB2 axis. TUG1 might worked as a ceRNA to sponge miR186, TUG1 mediated MTX resistance in CRC cells via suppressing miR186.
Liver cancer [ICD-11: 2C12]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Glyceraldehyde-3-phosphate dehydrogenase 1 (GAPDH) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Hexokinase-2 (HK2) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Isocitrate dehydrogenase NAD 3 alpha (IDH3A) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Solute carrier family 16 member 1 (SLC16A1) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Solute carrier family 16 member 3 (SLC16A3) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Phosphofructo-1-kinase isozyme B (PFKB) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Pyruvate kinase M2 (PKM) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.
Key Molecule: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit (SDHB) [22]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Curcumin was able to induce SDH expression and repress the IDH3a in HepG2 cells both in a normal or elevated level of glucose. Such changes in SDH and IDH3a levels can bring a reduction in the succinate accumulation and hindering the succinate-HIF-1alpha axis. The augmented expression of HIF-1alpha in high glucose conditions was resisted by curcumin. HIF-1alpha is known for metabolic regulation in malignant cells, their hyperglycolytic behavior, and the onset of chemoresistance. HIF-1 exerts protumor effects through the upregulated expression of enzymes and transporters favoring the hyperglycolytic and therapy-resistant phenotype.
Lung cancer [ICD-11: 2C25]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-200c [23]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
P53/P21/EZH2/E-cad signaling pathway Activation hsa04115
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Transwell assay
Mechanism Description Over expression of miR-200c reduced the resistance of A549/MTX cells to MTX with the mechanism of inducing apoptosis through the P53/P21 pathway.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Ribonuclease P protein subunit p21 (RPP21) [23]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
P53/P21/EZH2/E-cad signaling pathway Activation hsa04115
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Transwell assay
Mechanism Description Over expression of miR-200c reduced the resistance of A549/MTX cells to MTX with the mechanism of inducing apoptosis through the P53/P21 pathway.
Key Molecule: Cellular tumor antigen p53 (TP53) [23]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
P53/P21/EZH2/E-cad signaling pathway Activation hsa04115
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Transwell assay
Mechanism Description Over expression of miR-200c reduced the resistance of A549/MTX cells to MTX with the mechanism of inducing apoptosis through the P53/P21 pathway.
Gestational trophoblastic neoplasia [ICD-11: 2C75]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: SRY-box transcription factor 8 (SOX8) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Gestational trophoblastic neoplasia [ICD-11: 2C75.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell viability Activation hsa05200
Cell apoptosis Inhibition hsa04210
In Vitro Model JEG3 cells Brain Homo sapiens (Human) CVCL_0363
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description Over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells.
Key Molecule: SRY-box transcription factor 8 (SOX8) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Gestational trophoblastic neoplasia [ICD-11: 2C75.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell viability Activation hsa05200
Cell apoptosis Inhibition hsa04210
In Vitro Model JEG3 cells Brain Homo sapiens (Human) CVCL_0363
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description Over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells.
ICD-04: Immune system diseases
Click to Show/Hide the Resistance Disease of This Class
Lupus erythematosus [ICD-11: 4A40]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Systemic lupos erythematosus [ICD-11: 4A40.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description Up-regulation of P-glycoprotein led to methotrexate resistance in the staphylococcus infection.
ICD-14: Skin diseases
Click to Show/Hide the Resistance Disease of This Class
Psoriasis [ICD-11: EA90]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [7]
Molecule Alteration SNP
rs1045642 TT
 Molecule Info 
Resistant Disease Psoriasis [ICD-11: EA90.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description The SNP of ABCB1 led to methotrexate resistance in the resistance.
ICD-15: Musculoskeletal/connective-tissue diseases
Click to Show/Hide the Resistance Disease of This Class
Rheumatoid arthritis [ICD-11: FA20]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [8]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Rheumatoid arthritis [ICD-11: FA20.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cellular tumor antigen p53 (TP53) [8]
Molecule Alteration Mutation
p.P151S+p.R175H+p.G245C+p.R282W
 Molecule Info 
Resistant Disease Rheumatoid arthritis [ICD-11: FA20.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description The wild-type p53 tumor suppressor (p53) is overexpressed in response to DNA damage and inflammation in RA fibroblast-like synoviocytes (FLS), which are highly specialized mesenchymal cells located in the internal lining of the synovium and are involved in the pathogenesis and progression of RA. In line with the effects of p53 gain-of-function mutation in tumor progression, mutation-mediated gain-of-function of p53 may contribute to the invasiveness and apoptosis-resistant feature of FLS in RA and the increased expression of cartilage degradative proteases, leading to degeneration of cartilage and bone. Gene knockout or gene transfer studies using a collagen-II-induced arthritis (CIA) model have established the crucial role of p53 in RA that provides a basis for additional research to fully characterize the clinical implications of p53 somatic mutations in drug-resistant RA.
References
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