Drug Information

Drug (ID: DG01716) and It's Reported Resistant Information

• Name: AZD3463/Doxorubicin
• Synonyms: AZD3463/Doxorubicin

Type(s) of Resistant Mechanism of This Drug

  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

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Proto-oncogene serine/threonine-protein kinase Pim (PIM kinase) [1]

• Sensitive Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SK-N-BE cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In the current study, we explore how PIM kinase correlates with the MRP1 drug efflux pump. We demonstrate that PIM kinase inhibition modulates the function of MRP1 mediated efflux of doxorubicin in neuroblastoma.?

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: ALK tyrosine kinase receptor (ALK) [2]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.D1091N (c.3271G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: LA-N-6 cells; Bone marrow; Homo sapiens (Human); CVCL_1363
• In Vivo Model: Athymic NCR nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay; FACS assay; Propidium iodide staining assay; MTT assay
• Mechanism Description: The novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time.

References

• Ref 1: PIM Kinase Inhibition Sensitizes Neuroblastoma to Doxorubicin. J Pediatr Surg. 2024 Jul;59(7):1334-1341.
• Ref 2: The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse modelCancer Lett. 2017 Aug 1;400:61-68. doi: 10.1016/j.canlet.2017.04.022. Epub 2017 Apr 26.