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Necrocide 1 mediates necrotic cell death and immunogenic response in human cancer cells

Jing Zhang1, Christina Trojel-Hansen2,3, Jianghuang Wang4

  • 1Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. jingzhang@shsmu.edu.cn.

Cell Death & Disease
|April 4, 2023
PubMed

Insights

A novel compound, necrocide-1 (NC1), selectively kills cancer cells via a unique necrotic pathway. This tumor necrosis factor-independent mechanism involves mitochondria and triggers an immunogenic cell death response, offering a new anticancer therapy strategy.

Area of Science:

  • Oncology
  • Cell Biology
  • Immunology

Background:

  • Anticancer agents commonly induce apoptosis, mitotic catastrophe, or senescence.
  • Targeting cancer cell death pathways is crucial for effective therapy.

Purpose of the Study:

  • To functionally characterize necrocide-1 (NC1), an experimental inducer of tumor necrosis factor (TNF)-independent necrosis.
  • To elucidate the mechanism of NC1-induced cancer cell death and its therapeutic potential.

Main Methods:

  • In vitro and in vivo studies using a panel of human cancer cells and normal cells.
  • Assessment of cell death morphotype, inhibition studies with caspase blockers, BCL2 overexpression, and TNFα neutralization.
  • Pharmacological and genetic inhibition of necroptosis, pyroptosis, and ferroptosis.
  • Mitochondrial reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) analysis.
  • Cyclosporine A treatment to block mitochondrial permeability transition.
  • Analysis of immunogenic cell death markers: calreticulin (CALR) exposure, ATP secretion, and high mobility group box 1 (HMGB1) release.

Main Results:

  • NC1 selectively killed cancer cells (but not normal cells) at nanomolar concentrations via necrosis, independent of TNFα.
  • NC1-induced cell death was not blocked by inhibiting apoptosis, necroptosis, pyroptosis, or ferroptosis.
  • NC1 triggered mitochondrial ROS production and its inhibition affected cell death.
  • NC1 induced hallmarks of immunogenic cell death, including CALR exposure, ATP secretion, and HMGB1 release.

Conclusions:

  • NC1 elicits a novel, TNF-independent necrotic pathway regulated by mitochondria.
  • This pathway is distinct from known forms of regulated cell death (necroptosis, pyroptosis, ferroptosis).
  • NC1 induces immunogenic cell death, suggesting its potential as a novel anticancer therapeutic agent.

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