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Background <p>Lung cancer continues to rank as a leading cause of cancer-related mortality worldwide. Despite notable advances in medical research, therapeutic options for advanced-stage lung cancer remain inadequate. Heat shock protein 90 (HSP90) has been identified as a potential therapeutic target in multiple malignancies, such as lung and colon cancers, owing to its pivotal role in stabilizing numerous oncoproteins. Nonetheless, the clinical application of HSP90 inhibitors has faced challenges, including suboptimal efficacy and the development of resistance mechanisms. B-AP15 is a promising small molecule in cancer therapy that functions by inhibiting deubiquitinating enzymes, which regulate protein degradation through the proteasome pathway. In this study, we aim to investigate its combinatorial activity with the HSP90 inhibitor tanespimycin (TAU) in lung cancer cells.</p> Methods <p>The levels of the specified molecules were measured by Western blot analysis. Reactive oxygen species (ROS) levels were determined using the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. 53BP1 foci formation and C/EBP homologous protein (CHOP) expression were assessed by immunofluorescence. Autophagic flux was monitored using mRFP-GFP-tagged microtubule-associated protein 1 light chain 3 (LC3) lentivirus.</p> Results <p>Our findings reveal that the combination of TAU and B-AP15 induces significant synergistic antitumor effects, characterized by substantial accumulation of ROS. This ROS accumulation serves as a crucial mediator of the enhanced therapeutic response elicited by the combination treatment. Mechanistic analyses further demonstrated that the combined treatment induces cell death via activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway.</p> Conclusion <p>In summary, our study provides robust evidence supporting the potential of combining TAU with B-AP15 as a viable therapeutic option for lung cancer treatment.</p>

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Combination of B-AP15 and HSP90 inhibitor tanespimycin induces ROS-mediated cytotoxicity in human lung cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月28日

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  • Wenying Fu,
  • Hui Lu,
  • Ying Yan,
  • Chongchong Shu,
  • Chenxin Xu,
  • Yinghua Chen,
  • Yiqun Xia,
  • Jundixia Chen,
  • Yunzhi Chen,
  • Peng Zou,
  • Ri Cui,
  • Daoyong Ni

摘要

Background

Lung cancer continues to rank as a leading cause of cancer-related mortality worldwide. Despite notable advances in medical research, therapeutic options for advanced-stage lung cancer remain inadequate. Heat shock protein 90 (HSP90) has been identified as a potential therapeutic target in multiple malignancies, such as lung and colon cancers, owing to its pivotal role in stabilizing numerous oncoproteins. Nonetheless, the clinical application of HSP90 inhibitors has faced challenges, including suboptimal efficacy and the development of resistance mechanisms. B-AP15 is a promising small molecule in cancer therapy that functions by inhibiting deubiquitinating enzymes, which regulate protein degradation through the proteasome pathway. In this study, we aim to investigate its combinatorial activity with the HSP90 inhibitor tanespimycin (TAU) in lung cancer cells.

Methods

The levels of the specified molecules were measured by Western blot analysis. Reactive oxygen species (ROS) levels were determined using the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. 53BP1 foci formation and C/EBP homologous protein (CHOP) expression were assessed by immunofluorescence. Autophagic flux was monitored using mRFP-GFP-tagged microtubule-associated protein 1 light chain 3 (LC3) lentivirus.

Results

Our findings reveal that the combination of TAU and B-AP15 induces significant synergistic antitumor effects, characterized by substantial accumulation of ROS. This ROS accumulation serves as a crucial mediator of the enhanced therapeutic response elicited by the combination treatment. Mechanistic analyses further demonstrated that the combined treatment induces cell death via activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway.

Conclusion

In summary, our study provides robust evidence supporting the potential of combining TAU with B-AP15 as a viable therapeutic option for lung cancer treatment.