Disease Information

General Information of the Disease (ID: DIS00505)

• Name: Chronic myeloid leukemia
• ICD: ICD-11: 2A20

Type(s) of Resistant Mechanism of This Disease

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 7 drug(s) in total

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562-ABCG2 cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of ABCG2 on the membrane surface of CML cells contributes to decreased TKI efficacy. This study demonstrates for the first time that the concomitant use of febuxostat enhances the efficacy of dasatinib in patients with CML. This is at least, in part, by the inhibition of ABCG2-mediated dasatinib excretion from CML cells.

Daunorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: microRNA-18a-5p (miR-18a-5p) [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Daunorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/ADM cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K563 cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: These results provided new evidence that miR-18a-5p may suppress the Warburg effect by targeting HIF-1alpha.Cells transfected with miR-18a-5p mimics were more sensitive to Adriamycin (AMD) compared with AMD group.

Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1) [4]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Daunorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/ADMR cells; Blood; Homo sapiens (Human); CVCL_5950
• Experiment for Molecule Alteration: Expression profiles
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCB1 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: The ABC transporters are responsible for the efflux of a wide range of chemotherapeutics across the plasma membrane, leading to lower intracellular drug levels and treatment resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCG2 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Induction of DNA double-strand breaks and chromatin damage through histone eviction;Less affected by ABCG2-mediated drug export.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1) [4]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Expression profiles
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

Idarubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Idarubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCG2 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Induction of DNA double-strand breaks and chromatin damage through histone eviction;Less affected by ABCG2-mediated drug export.

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

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Idarubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCB1 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Induction of DNA double-strand breaks and chromatin damage through histone eviction.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562-ABCG2 cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of ABCG2 on the membrane surface of CML cells contributes to decreased TKI efficacy. This study demonstrates for the first time that the concomitant use of febuxostat enhances the efficacy of dasatinib in patients with CML. This is at least, in part, by the inhibition of ABCG2-mediated dasatinib excretion from CML cells.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Thioredoxin interacting protein (TXNIP) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: kCL22 cells; Pleural effusion; Homo sapiens (Human); CVCL_2091
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Here, we demonstrate that TXNIP expression was decreased in response to the activated BCR-ABL signaling, which is associated with a previously unappreciated mechanism that involves in c-Myc/Miz-1/P300 complex. Restoration of TXNIP expression sensitizes CML cells to imatinib treatment, potentially through the blockage of glucose metabolism. In particular, TXNIP suppressed glycolytic enzyme expressions through Fbw7-dependent c-Myc degradation. BCR-ABL suppression of TXNIP provided a novel survival pathway for CML transformation.

Key Molecule: Thioredoxin interacting protein (TXNIP) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, with K562 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell colony formation assay
• Mechanism Description: Here, we demonstrate that TXNIP expression was decreased in response to the activated BCR-ABL signaling, which is associated with a previously unappreciated mechanism that involves in c-Myc/Miz-1/P300 complex. Restoration of TXNIP expression sensitizes CML cells to imatinib treatment, potentially through the blockage of glucose metabolism. In particular, TXNIP suppressed glycolytic enzyme expressions through Fbw7-dependent c-Myc degradation. BCR-ABL suppression of TXNIP provided a novel survival pathway for CML transformation.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1) [4]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/OxR cells; Blood; Homo sapiens (Human); CVCL_0248
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Expression profiles
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

Investigative Drug(s) 1 drug(s) in total

Anthracyclines

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Anthracyclines
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCG2 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Exert their activity exclusively through histone eviction and are generally more cytotoxic to tumor cells than their parent compound;DNA double-strand break generation versus histone eviction;Anthracyclines featuring an N,N-dimethyl aminosugar in general are poor substrates for the ABCB1 drug transporter as compared to their non-alkylated counterparts.

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

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Anthracyclines
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCB1 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Exert their activity exclusively through histone eviction and are generally more cytotoxic to tumor cells than their parent compound;DNA double-strand break generation versus histone eviction;Anthracyclines featuring an N,N-dimethyl aminosugar in general are poor substrates for the ABCB1 drug transporter as compared to their non-alkylated counterparts.

References

• Ref 1: Novel N,N-Dimethyl-idarubicin Analogues Are Effective Cytotoxic Agents for ABCB1-Overexpressing, Doxorubicin-Resistant Cells. J Med Chem. 2024 Aug 22;67(16):13802-13812.
• Ref 2: Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells. Biomed Pharmacother. 2024 Dec;181:117709.
• Ref 3: MicroRNA-18a-5p regulates the Warburg effect by targeting hypoxia-inducible factor 1alpha in the K562/ADM cell line. Exp Ther Med. 2021 Oct;22(4):1069.
• Ref 4: PKM1 is involved in resistance to anti-cancer drugs. Biochem Biophys Res Commun. 2016 Apr 22;473(1):174-180.
• Ref 5: BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP. Cell Death Dis. 2023 Apr 24;14(4):287.