Molecule Information

General Information of the Molecule (ID: Mol00005)

• Name: ATP-binding cassette sub-family G2 (ABCG2) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: ABCG2
• Gene ID: 9429
• Location: chr4:88090150-88231628[-]
• Sequence:
  MSSSNVEVFIPVSQGNTNGFPATASNDLKAFTEGAVLSFHNICYRVKLKSGFLPCRKPVE
  KEILSNINGIMKPGLNAILGPTGGGKSSLLDVLAARKDPSGLSGDVLINGAPRPANFKCN
  SGYVVQDDVVMGTLTVRENLQFSAALRLATTMTNHEKNERINRVIQELGLDKVADSKVGT
  QFIRGVSGGERKRTSIGMELITDPSILFLDEPTTGLDSSTANAVLLLLKRMSKQGRTIIF
  SIHQPRYSIFKLFDSLTLLASGRLMFHGPAQEALGYFESAGYHCEAYNNPADFFLDIING
  DSTAVALNREEDFKATEIIEPSKQDKPLIEKLAEIYVNSSFYKETKAELHQLSGGEKKKK
  ITVFKEISYTTSFCHQLRWVSKRSFKNLLGNPQASIAQIIVTVVLGLVIGAIYFGLKNDS
  TGIQNRAGVLFFLTTNQCFSSVSAVELFVVEKKLFIHEYISGYYRVSSYFLGKLLSDLLP
  MRMLPSIIFTCIVYFMLGLKPKADAFFVMMFTLMMVAYSASSMALAIAAGQSVVSVATLL
  MTICFVFMMIFSGLLVNLTTIASWLSWLQYFSIPRYGFTALQHNEFLGQNFCPGLNATGN
  NPCNYATCTGEEYLVKQGIDLSPWGLWKNHVALACMIVIFLTIAYLKLLFLKKYS
• Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells. Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme. Also mediates the efflux of sphingosine-1-P from cells. Acts as a urate exporter functioning in both renal and extrarenal urate excretion. In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate. Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates. Mediates the secretion of the riboflavin and biotin vitamins into milk. Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability. Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux. In placenta, it limits the penetration of drugs from the maternal plasma into the fetus. May play a role in early stem cell self-renewal by blocking differentiation.
• Uniprot ID: ABCG2_HUMAN
• Ensembl ID: ENSG00000118777
• HGNC ID: HGNC:74

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 23 drug(s) in total

Carboplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Retinoblastoma [1]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Celecoxib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Rheumatoid arthritis [2]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Resistant Drug: Celecoxib
• Molecule Alteration: Expression; Up-regulation
• 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.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Activation; hsa04110
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-106a promotes breast cancer cell proliferation and invasion through upregulation of Bcl-2, ABCG2, and P53, and downregulation of Bax and RUNX3.

Disease Class: Sarcoma [4]

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

Disease Class: Oral cancer [5]

• Resistant Disease: Oral cancer [ICD-11: 2B6E.1]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UM-SCC-1 cells; Ovary; Homo sapiens (Human); CVCL_7707
• In Vitro Model: WSU-HN30 cells; Pleural effusion; Homo sapiens (Human); CVCL_5525
• In Vitro Model: WSU-HN6 cells; Urinary bladder; Homo sapiens (Human); CVCL_5516
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: E-cigarette aerosol exposure alters the expression of drug influx and efflux transporters.Among the other drug efflux ATPase genes previously reported to contribute to cisplatin resistance ABCG2, ABCC2, ABCA1, and ABCC1 were significantly up-regulated in at least one cell line.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Gastric cancer [6]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SIRT1/CREB/ABCG2 signaling pathway; Regulation; hsa05200
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulated miR132 in Lgr5+ gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription.

Disease Class: Retinoblastoma [1]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Daunorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [7]

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

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer bone metastasis [8]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Studies have shown that resistance can occur from altered expression of apoptosis regulatory proteins (p53, Bcl-2), and overexpression of ATP binding cassette (ABC) transporters/ multidrug resistance-related proteins such as multidrug resistance-associated protein 1 (MRP1), ATP-binding cassette super-family G member 2 (ABCG2).

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Esophageal cancer [9]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: Flow cytometry assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Extracellular vesicles released by drug-resistant cells were proved that they could upregulate the expression of ABCG2 in esophageal cancer cells and thus regulate the drug resistance of esophageal cancer cells, which was related to the linc-VLDLR carried by EVs.

Disease Class: Hepatocellular cancer [10]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Disease Class: Breast cancer [7]

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

Disease Class: Sarcoma [4]

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Retinoblastoma [1]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Disease Class: Lung cancer [11]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• 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
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Suppression of miR-155 in this cell line considerably reversed doxorubicin resistance, and doxorubicin-induced apoptosis and cell cycle arrest were recovered. Furthermore, reverse transcription-polymerase chain reaction and western blot analysis revealed that miR-155 suppression downregulated the expression of multidrug resistance protein 1, multidrug resistance-associated protein 1, breast cancer resistance protein, glutathione S-transferase-Pi, Survivin and B-cell lymphoma 2, and upregulated the expression of caspase-3 and caspase-8. In addition, it was found that miR-155 suppression inhibited the activation of AkT and extracellular signal-regulated kinase. The transcriptional activity of nuclear factor-kB and activator protein-1 was also downregulated.

Disease Class: Ovarian cancer [12]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Disease Class: Breast cancer [12]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Disease Class: Liver cancer [12]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Epirubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Sarcoma [4]

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

Etoposide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Retinoblastoma [1]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Sensitive Drug: Etoposide
• Molecule Alteration: Expression; Down-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Colon cancer [13]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Natural killer/T-cell lymphoma [14]

• Resistant Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ABCG2 upregulated cell proliferation, increased clonogenicity, increased invasive ability and decreased apoptosis, in vivo and in vitro, when cells were treated with gemcitabine.

Disease Class: Natural killer/T-cell lymphoma [14]

• Resistant Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ABCG2 upregulated cell proliferation, increased clonogenicity, increased invasive ability and decreased apoptosis, in vivo and in vitro, when cells were treated with gemcitabine.

Glucosamine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [15]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Glucosamine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: MDA PCa 2b cells; Prostate; Homo sapiens (Human); CVCL_4748
• Experiment for Molecule Alteration: Quantitative RT-PCR assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry
• Mechanism Description: This study was aimed at investigating the cytotoxicity and multi-drug resistance (MDR) reversal effect of Glucosamine (GlcN) on resistant BCRP-overexpressing breast cancer MCF-7/MX cells. These results proposed that glucosamine as a natural sugar could down regulate the BCRP expression and increased MX cytotoxicity in breast cancer cells. These results proposed that glucosamine as a natural sugar could down regulate the BCRP expression and increased MX cytotoxicity in breast cancer cells.

Imatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Chronic myeloid leukemia [16]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Imatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC/PI Apoptosis Detection assay
• Mechanism Description: Overexpression of MEG3 in imatinib-resistant k562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2.

Leflunomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Rheumatoid arthritis [2]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Resistant Drug: Leflunomide
• Molecule Alteration: Expression; Up-regulation
• 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.

Mitoxantrone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [17]

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

Disease Class: Breast cancer [17]

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

Disease Class: Breast cancer [18]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Mitoxantrone
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/MX100 cells; Breast; Homo sapiens (Human); CVCL_LB54
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Sulforhodamine B assay
• Mechanism Description: miR-328 targets ABCG2 3'-UTR and, consequently, controls ABCG2 protein expression and influences drug disposition in human breast cancer cells. miR-328-directed down-regulation of ABCG2 expression in MCF-7/MX100 cells resulted in an increased mitoxantrone sensitivity.

Disease Class: Breast cancer [7]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Mitoxantrone
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/AdrVp cells; Breast; Homo sapiens (Human); CVCL_4Y46
• In Vitro Model: MCF-7/AdrVpPR cells; Breast; Homo sapiens (Human); CVCL_4Y46
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Flow cytometric assay
• Mechanism Description: The overexpression of BCRP mRNA in MCF-7/AdrVp cells, which is diminished in MCF-7/AdrVpPR, suggests an important role for BCRP in resistance to cytotoxic agents. Furthermore, the enforced overexpression of BCRP in MCF-7 cells diminished daunorubicin cellular accumulation and imparted a pattern of drug crossresistance to the transfected cells that was virtually identical to that of MCF-7/AdrVp.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [19]

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

Disease Class: Breast cancer [20]

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

Disease Class: Breast cancer [20]

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

Disease Class: Chronic myeloid leukemia [21]

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

Disease Class: Solid tumour/cancer [22]

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

Disease Class: Solid tumour/cancer [22]

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

Disease Class: Solid tumour/cancer [22]

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

Disease Class: Solid tumour/cancer [22]

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

Disease Class: Solid tumour/cancer [23]

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

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [24]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7/PR cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Sulforhodamine B assay
• Mechanism Description: Down-regulation of LncRNA RP11-770J1.3 and TMEM25 enhanced the sensitivity of MCF-7/PR cells to paclitaxel, and inhibited the expression of MRP, BCRP and MDR1/P-gp.

Perphenazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Glioblastoma [25]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Perphenazine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The present study explored the effects of perphenazine and prochlorperazine on the levels of ABCB1, ABCG2, E-cadherin, alpha-tubulin and integrins (alpha3, alpha5, and beta1), as well as on the migratory and invasive ability of U87-MG cells. The results suggested that perphenazine and prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Prochlorperazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Glioblastoma [25]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Prochlorperazine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis; RNA-sequencing analysis
• Experiment for Drug Resistance: Wound healing assay;Transwell assay
• Mechanism Description: Prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Rosuvastatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Hyperlipidemia [26], [27]

• Sensitive Disease: Hyperlipidemia [ICD-11: 5C80.Z]
• Sensitive Drug: Rosuvastatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Enasidenib (and its metabolite, AGI-16903) at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-gp, BCRP, OATP1B1, and OATP1B3 transporters. When a single dose of rosuvastatin was administered together with 28 days of dosing of enasidenib, the AUC0-30 and AUC0-inf of rosuvastatin increased by =249% and 244%, respectively; and the Cmax increased by 366%, when compared to the single dose of rosuvastatin administered alone.

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Hepatocellular cancer [10]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Disease Class: Hepatocellular carcinoma [10]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Sulfasalazine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Rheumatoid arthritis [2]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Resistant Drug: Sulfasalazine
• Molecule Alteration: Expression; Up-regulation
• 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Ulcerative colitis [26]

• Sensitive Disease: Ulcerative colitis [ICD-11: DD71.0]
• Sensitive Drug: Sulfasalazine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: IPS cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Ussing chamber system assay
• Mechanism Description: Digoxin and fexofenadine (each 5 uM) were selected as P-gp substrates, and sulfasalazine and rosuvastatin (each 5 uM) were selected as BCRP substrates to evaluate the efflux transport mediated by P-gp and BCRP. PSC833 (15 uM) and ko143 (15 uM) were used as typical inhibitors of P-gp and BCRP, respectively. Serosal-to-mucosal transport of all the tested P-gp and BCRP substrate drugs was significantly decreased or tended to decrease in the presence of P-gp/BCRP inhibitor cocktail.

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malignant glioma [28]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Teriflunomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Multiple sclerosis [29]

• Sensitive Disease: Multiple sclerosis [ICD-11: 8A40.0]
• Sensitive Drug: Teriflunomide
• Molecule Alteration: Expression; Down-regulation
• 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: C57BL/6J cells(Mus musculus (Mouse)); Lymph; Homo sapiens (Human); CVCL_5U84
• In Vivo Model: EAE mice model; Mus musculus
• Experiment for Drug Resistance: Annexin V staining assay
• Mechanism Description: In vitro, intracellular teri concentration in T cells was 2.5-fold higher in abcg2-kO mice than in wt mice. Teri-induced inhibition of T cell proliferation was two fold increased in abcg2-kO cells compared to wt.

Disease Class: Multiple sclerosis [29]

• Sensitive Disease: Multiple sclerosis [ICD-11: 8A40.0]
• Sensitive Drug: Teriflunomide
• Molecule Alteration: Expression; Down-regulation
• 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: C57BL/6J cells(Mus musculus (Mouse)); Lymph; Homo sapiens (Human); CVCL_5U84
• In Vivo Model: EAE mice model; Mus musculus
• Experiment for Drug Resistance: Annexin V staining assay
• Mechanism Description: Pharmacological abcg2 inhibition in T cells from wt mice led to an increase of teri-induced apoptosis (Ko143 vs. DMSO: 3.1-fold, p < 0.05; FTC vs. DMSO: 2.8-fold, p > 0.05).

Vincristine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Retinoblastoma [1]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Sensitive Drug: Vincristine
• Molecule Alteration: Expression; Down-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Clinical Trial Drug(s) 2 drug(s) in total

Camptothecin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Hepatocellular cancer [10]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Resistant Drug: Camptothecin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Hydroxycamptothecin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Colorectal cancer [30]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Hydroxycamptothecin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MMP16 is one member of the matrix metalloproteinase (MMP) family and can degrade type III collagen, gelatin, fibronectin and laminin-1, enhance the growth and invasiveness. ABCG2 is a member of ATP-binding cassette transporters. miR-328 downregulation may contribute to the overexpression of ABCG2 and MMP16 and cause drug resistance.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.63E-03; Fold-change: -2.10E-01; Z-score: -2.66E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.87E-01; Fold-change: -2.51E-01; Z-score: -3.23E-01
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.24E-02; Fold-change: -8.49E-01; Z-score: -5.22E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.01E-01; Fold-change: -2.88E-01; Z-score: -6.33E-01

Chronic myeloid leukemia [ICD-11: 2A20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Myelofibrosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.22E-03; Fold-change: 1.38E+00; Z-score: 4.26E+00
• The Studied Tissue: Whole blood
• The Specified Disease: Polycythemia vera
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.04E-15; Fold-change: 5.83E-01; Z-score: 1.90E+00

Oral squamous cell carcinoma [ICD-11: 2B6E]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Oral tissue
• The Specified Disease: Oral squamous cell carcinoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.32E-01; Fold-change: 3.44E-01; Z-score: 4.51E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.29E-03; Fold-change: -3.08E-01; Z-score: -6.42E-01

Esophageal cancer [ICD-11: 2B70]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Esophagus
• The Specified Disease: Esophageal cancer
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.82E-01; Fold-change: -3.51E-01; Z-score: -4.33E-01

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.57E-03; Fold-change: 1.18E+00; Z-score: 6.01E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.31E-01; Fold-change: 7.41E-01; Z-score: 5.74E-01

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.83E-95; Fold-change: -5.61E+00; Z-score: -4.08E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.43E-51; Fold-change: -4.63E+00; Z-score: -2.62E+00

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.85E-09; Fold-change: -1.57E+00; Z-score: -1.47E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.18E-31; Fold-change: -1.31E+00; Z-score: -1.79E+00
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 2.57E-02; Fold-change: -1.38E+00; Z-score: -2.02E+00

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.87E-47; Fold-change: -1.28E+00; Z-score: -1.63E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.29E-43; Fold-change: -1.56E+00; Z-score: -2.12E+00

Sarcoma [ICD-11: 2C35]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Muscle
• The Specified Disease: Sarcoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.58E-56; Fold-change: 5.96E-01; Z-score: 1.15E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.57E-05; Fold-change: 6.59E-01; Z-score: 5.57E+00

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.46E-65; Fold-change: -1.41E+00; Z-score: -1.41E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.44E-13; Fold-change: -1.33E+00; Z-score: -1.59E+00

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.76E-03; Fold-change: -1.19E+00; Z-score: -1.71E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.34E-02; Fold-change: -5.11E-01; Z-score: -7.50E-01

Retina cancer [ICD-11: 2D02]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Uvea
• The Specified Disease: Retinoblastoma tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.43E-02; Fold-change: -3.15E-01; Z-score: -6.12E-01

ICD Disease Classification 05

Hyperlipoproteinaemia [ICD-11: 5C80]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Familial hypercholesterolemia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.28E-08; Fold-change: -3.66E-01; Z-score: -8.07E-01

ICD Disease Classification 08

Multiple sclerosis [ICD-11: 8A40]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Plasmacytoid dendritic cells
• The Specified Disease: Multiple sclerosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.93E-01; Fold-change: -1.09E-01; Z-score: -5.77E-01
• The Studied Tissue: Spinal cord
• The Specified Disease: Multiple sclerosis
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.64E-01; Fold-change: 1.69E-02; Z-score: 1.22E-02

ICD Disease Classification 13

Ulcerative colitis [ICD-11: DD71]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon mucosa
• The Specified Disease: Ulcerative colitis
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.91E-02; Fold-change: -2.00E+00; Z-score: -1.13E+00

ICD Disease Classification 15

Rheumatoid arthritis [ICD-11: FA20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Peripheral blood
• The Specified Disease: Rheumatoid arthritis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.69E-07; Fold-change: 1.39E-01; Z-score: 3.45E-01
• The Studied Tissue: Synovial tissue
• The Specified Disease: Rheumatoid arthritis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.63E-01; Fold-change: -1.31E-01; Z-score: -2.30E-01

References

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