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Background <p>Glioma is a highly aggressive brain tumor with few therapy options. Temozolomide (TMZ) is a standard chemotherapeutic medication, although its effectiveness is limited by innate and acquired drug resistance.</p> Methods <p>A series of functional properties were assessed using established glioma cell lines (U87, LN229) and patient-derived subtypes, to investigate cell survival, colony formation, apoptosis, EdU incorporation, and cell cycle distribution. Treatment responses were assessed in a therapeutically relevant setting using glioma organoid models to investigate the synergistic effects of JJH201601 with TMZ, a CDC7 inhibitor (XL413), and a CDK4/6 inhibitor (palbociclib). For pharmacological investigations, glioma xenograft models in nude mice were created by inoculating U87 cells subcutaneously.</p> Results <p>JJH201601 dramatically reduced cell viability, induced apoptosis, and caused G1/S transition dysregulation with S-phase accumulation in glioma cells. It suppressed ribosome-related genes (RPL13, RPS9, and RPS27L) while activating the p53 signaling pathway. The combination therapy with TMZ had a synergistic inhibitory effect on tumor growth in both cell lines and glioma organoids. JJH201601 boosted the antiproliferative effects of CDK4/6 and CDC7 inhibitors by lowering Ki-67 expression and disrupting cell cycle checkpoint regulation. JJH201601 has an impact on key glioma cell survival regulators, including CDK2, γ-H2AX, and MCM2, as determined by transcriptome analyses. JJH201601 also had a substantial inhibitory effect on recurrent primary glioma cells.</p> Conclusions <p>JJH201601 exhibited anti-glioma activity by suppressing proliferation, promoting apoptosis, affecting ribosome biogenesis-related signaling, and disrupting cell cycle regulation. Its combination with TMZ and selected cell cycle inhibitors showed enhanced inhibitory effects in preclinical glioma models. However, current in vivo evidence is restricted to a subcutaneous xenografts, further orthotopic intracranial glioma studies with pharmacokinetic profiling and comprehensive safety assessments are required to confirm its efficacy for resistant glioma.</p>

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Antitumor effects of the novel docetaxel derivative JJH201601 in glioma: targeting ribosome biogenesis and enhancing temozolomide sensitivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Ruiqi Jiang,
  • Mingnan Cao,
  • Dan Liu,
  • Meiyu Shang,
  • Shenghui Mei,
  • Shuxian Yang,
  • Luofei Zhang,
  • Nan Ji,
  • Zhigang Zhao

摘要

Background

Glioma is a highly aggressive brain tumor with few therapy options. Temozolomide (TMZ) is a standard chemotherapeutic medication, although its effectiveness is limited by innate and acquired drug resistance.

Methods

A series of functional properties were assessed using established glioma cell lines (U87, LN229) and patient-derived subtypes, to investigate cell survival, colony formation, apoptosis, EdU incorporation, and cell cycle distribution. Treatment responses were assessed in a therapeutically relevant setting using glioma organoid models to investigate the synergistic effects of JJH201601 with TMZ, a CDC7 inhibitor (XL413), and a CDK4/6 inhibitor (palbociclib). For pharmacological investigations, glioma xenograft models in nude mice were created by inoculating U87 cells subcutaneously.

Results

JJH201601 dramatically reduced cell viability, induced apoptosis, and caused G1/S transition dysregulation with S-phase accumulation in glioma cells. It suppressed ribosome-related genes (RPL13, RPS9, and RPS27L) while activating the p53 signaling pathway. The combination therapy with TMZ had a synergistic inhibitory effect on tumor growth in both cell lines and glioma organoids. JJH201601 boosted the antiproliferative effects of CDK4/6 and CDC7 inhibitors by lowering Ki-67 expression and disrupting cell cycle checkpoint regulation. JJH201601 has an impact on key glioma cell survival regulators, including CDK2, γ-H2AX, and MCM2, as determined by transcriptome analyses. JJH201601 also had a substantial inhibitory effect on recurrent primary glioma cells.

Conclusions

JJH201601 exhibited anti-glioma activity by suppressing proliferation, promoting apoptosis, affecting ribosome biogenesis-related signaling, and disrupting cell cycle regulation. Its combination with TMZ and selected cell cycle inhibitors showed enhanced inhibitory effects in preclinical glioma models. However, current in vivo evidence is restricted to a subcutaneous xenografts, further orthotopic intracranial glioma studies with pharmacokinetic profiling and comprehensive safety assessments are required to confirm its efficacy for resistant glioma.