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Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities

Linnéa Ödborn Jönsson1, Maryam Sahi1, Ximena Lopez-Lorenzo1

  • 1Department of Women's and Children's Health, Karolinska Institutet, 171 64 Stockholm, Sweden.

International Journal of Molecular Sciences
|April 30, 2021
PubMed

Insights

Chemotherapy resistance in high-risk neuroblastoma (NB) is linked to cell cycle regulation. This study identified distinct cell cycle checkpoints and potential drug targets in TP53-mutated NB cell lines treated with doxorubicin.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Chemotherapeutics often target DNA integrity, triggering cell death via DNA damage responses linked to the cell cycle.
  • Disruptions in cell cycle regulation can lead to treatment resistance in cancer therapies.
  • Ultra high-risk neuroblastoma (NB) presents significant challenges in treatment efficacy.

Purpose of the Study:

  • To comprehensively analyze cell cycle checkpoint activation following doxorubicin treatment in TP53-mutated ultra high-risk neuroblastoma (NB) cell lines.
  • To identify potential druggable targets for overcoming treatment resistance.
  • To investigate checkpoint-dependent and independent mechanisms of drug response.

Main Methods:

  • Utilized flow cytometry, immunofluorescence, and live-cell imaging.
  • Analyzed a panel of TP53-mutated ultra high-risk NB cell lines (SK-N-DZ, Kelly, SK-N-AS, SK-N-FI, BE(2)-C).
  • Assessed cell cycle phase distribution and expression of key checkpoint proteins (phos-ATM, phos-CHK1, phos-CHK2, Wee1, p21, p27) post-doxorubicin treatment.

Main Results:

  • Doxorubicin treatment induced dose-dependent accumulation in S- and/or G2/M-phases.
  • Observed heterogeneous increases in cell cycle checkpoint proteins across different NB cell lines.
  • Combination treatments with doxorubicin and specific inhibitors (ATM, CHK1, Wee1, p21) showed varied delays in cell regrowth.
  • Identified a subset of cells with mitotic arrest, independent of intra-S- and G2/M-checkpoints.

Conclusions:

  • Distinct cell cycle checkpoints were mapped in ultra high-risk neuroblastoma cell lines.
  • Identified both checkpoint-dependent and independent druggable targets for potential therapeutic strategies.
  • Findings provide insights into mechanisms of doxorubicin resistance and suggest avenues for combination therapies.
Keywords:
ATMDNA damagecell cycle arrestdrug-resistancehigh-risk neuroblastomamitotic-arrestp21proliferation

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