ArticleScientific reports2025
PHD-2/HIF-1α axis mediates doxorubicin-induced angiogenesis in SH-SY5Y neuroblastoma microenvironment: a potential survival mechanism.
Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer.Angiogenesis · 2026Article
- Decoding macrophage heterogeneity in the pulmonary fibrosis lung cancer transition.Frontiers in immunology · 2026Review
- Amniotic membrane promotes doxorubicin potency by suppressing SH-SY5Y neuroblastoma cell angiogenesis.BMC cancer · 2025Article
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Authors and funding
10 authors.
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Abstract
The response of neuroblastoma (NB) cells to chemotherapeutics and their influence on NB microenvironment remain incompletely understood. Herein, we examined the underlying molecular mechanism via which Doxorubicin, a chemotherapeutic agent used for NB treatment, promotes proangiogenic response in the SH-SY5Y microenvironment. Doxorubicin treatment at 1 µg/ml reduced SH-SY5Y cell proliferation and primed the apoptosis pathway. Unexpectedly, SH-SY5Y cells treated with doxorubicin upregulated their expression of the pro-angiogenic factors, including vascular endothelial growth factor (VEGF), platelets-derived growth factor (PDGF), and matrix metalloprotease-2 (MMP-2) and secretion of nitric oxide. To assess the functional angiogenesis of SH-SY5Y cells pre-treated with doxorubicin, an indirect co-culture system with human umbilical vein endothelial cells (HUVEC) was established. These HUVECs acquired enhanced proliferation, migration capacity, and tube formation capability and exhibited increased nitric oxide (NO) production, in addition to upregulated α-smooth muscle actin expression, suggesting enhanced contractility. In-ovo studies of the neo-angiogenic response of SH-SY5Y pre-treated with doxorubicin further show their promoted neo-angiogenesis as indicated by the generated blood vessels and histological analysis of CD31 expression. Inhibition of PHD-2 could be a potential target for doxorubicin, as indicated by molecular docking, molecular dynamics (MD) simulation, and MM-GBSA calculations, leading to hypoxia-inducible factor-1 alpha (HIF-1α) stabilization. Bioinformatics analyses and enrichment analyses of RNA-seq data revealed activation of Pi3K pathway which is further validated in-vitro. These results provide evidence of the unexpected pro-angiogenic response of SH-SY5Y cells to doxorubicin treatment and suggest the potential use of multi-modal therapeutic regimens for a more comprehensive approach to NB treatment.
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