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<p>Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIP<sub>L</sub>, in the caspase-8/c-FLIP<sub>L</sub> heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated <i>via</i> an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIP<sub>L</sub> heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.</p>

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Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月3日

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  • Corinna König,
  • Nikita V. Ivanisenko,
  • Vladimir A. Ivanisenko,
  • Dagmar Kulms,
  • Inna N. Lavrik

摘要

Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIPL heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.