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Updated: May 29, 2025

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Camptothecin Triggers Apoptosis in Human and Mouse Drug-resistant Glioblastoma Cells via ROS-mediated Activation of

Gong-Jhe Wu1,2, Jui-Tai Chen3, Yih-Giun Cherng3,4

  • 1Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, R.O.C.

Anticancer Research
|January 31, 2025
PubMed
Abstract

Insights

Camptothecin (CPT) effectively induces apoptosis in drug-resistant glioblastoma cells. This occurs through reactive oxygen species and the p53-p21-CD1/CDK6-E2F1-Bcl-xL pathway, offering a potential new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
  • Temozolomide (TMZ) resistance is a major challenge in GBM therapy.
  • Camptothecin (CPT) and its nanoparticle CRLX101 previously showed efficacy against drug-sensitive GBM cells.

Purpose of the Study:

  • To evaluate the efficacy of CPT against drug-resistant GBM cells.
  • To elucidate the molecular mechanisms underlying CPT's action in resistant GBM.
  • To investigate the role of the p53-p21-cyclin D1 (CD1)/cyclin-dependent kinase 6 (CDK6)-E2F1-Bcl-xL signaling axis.

Main Methods:

  • Analyzed Topoisomerase I (Topo-1) gene expression in GBM using the UALCAN database.
  • Developed and treated TMZ-resistant human (U87MG-R) and mouse (GL261-R) GBM cell lines with CPT.
  • Assessed apoptotic events, intracellular reactive oxygen species (iROS), and key protein/gene expression levels.
  • Investigated the p53-p21-CD1/CDK6-E2F1-Bcl-xL signaling pathway and p53 transactivation activity.

Main Results:

  • Topo-1 gene expression was upregulated in human GBM.
  • CPT treatment reduced viability and induced apoptosis in resistant GBM cells, evidenced by caspase-3 activation and DNA fragmentation.
  • CPT increased intracellular reactive oxygen species (iROS), and blocking iROS attenuated CPT-induced apoptosis.
  • CPT upregulated p53 and p21 while downregulating CDK6, CD1, E2F1, and Bcl-xL.
  • Inhibition of p53 transactivation mitigated CPT-induced apoptosis.

Conclusions:

  • CPT effectively induces apoptosis in drug-resistant glioblastoma cells.
  • The mechanism involves iROS-mediated activation of the p53-p21-CD1/CDK6-E2F1-Bcl-xL axis.
  • CPT demonstrates potential as a therapeutic agent for TMZ-resistant GBM.
Keywords:
GlioblastomasapoptosiscamptotheciniROSp53-p21-CD1/CDK6-E2F1-Bcl-xL signaling axis

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