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<p>Colorectal cancer (CRC) remains a therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a camptothecin derivative engineered to target both topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the <i>hTERT</i> promoter G4, a regulator of telomere maintenance and oncogenic transcription. Structural studies reveal that&#xa0;the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the <i>hTERT</i> G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated improved efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a potential therapeutic strategy to enhance CRC chemosensitivity, presenting a new framework for combining DNA damage induction with transcription modulation.</p>

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Dual targeting of topoisomerase I and DNA G-quadruplexes enhances senescence and chemosensitivity in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Yameng Li,
  • Donglei Ji,
  • Yanjie Jia,
  • Yingying Liang,
  • Enwei Wei,
  • Chunfeng Gao,
  • Yongqi Li,
  • Caroline Zeng,
  • Liping Wang,
  • Chunyu Wang,
  • Zhen Guo,
  • Yiqun Zhang,
  • Ming-Ming Zhou,
  • Di Wu,
  • Lei Zeng

摘要

Colorectal cancer (CRC) remains a therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a camptothecin derivative engineered to target both topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a regulator of telomere maintenance and oncogenic transcription. Structural studies reveal that the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the hTERT G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated improved efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a potential therapeutic strategy to enhance CRC chemosensitivity, presenting a new framework for combining DNA damage induction with transcription modulation.