Disease Information

General Information of the Disease (ID: DIS00543)

• Name: Bladder cancer
• ICD: ICD-11: 2C94

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Rhodium trichloride hydrate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Urothelial carcinoma [ICD-11: 2C94.2]
• Resistant Drug: Rhodium trichloride hydrate
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: BALB/c-nu/nu mice, with UMUC3GR cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Urothelial carcinoma [ICD-11: 2C94.2]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: BALB/c-nu/nu mice, with UMUC3GR cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.

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

AGI-6780

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [1]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Urothelial carcinoma [ICD-11: 2C94.2]
• Sensitive Drug: AGI-6780
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: BALB/c-nu/nu mice, with UMUC3GR cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.

References

• Ref 1: IDH2 stabilizes HIF-1alpha-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. EMBO J. 2023 Feb 15;42(4):e110620.