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Fighting cancer by triggering non-canonical mitochondrial permeability transition-driven necrosis through reactive

Qingwen Xiao1, Bingling Zhong1, Ying Hou1

  • 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao.

Free Radical Biology & Medicine
|March 24, 2023
PubMed

Insights

Isoba vachalcone (IBC) induces non-apoptotic necrosis in cancer cells by triggering mitochondrial permeability transition (MPT) via reactive oxygen species (ROS). This cell death pathway, independent of cyclophilin D (CypD), offers a novel anticancer strategy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Non-apoptotic necrosis presents therapeutic potential, particularly in cancer treatment.
  • Mitochondrial permeability transition (MPT)-driven necrosis is a critical form of programmed cell death.
  • Isoba vachalcone (IBC), a natural chalcone, is known for inducing apoptosis in cancer cells.

Purpose of the Study:

  • To investigate the mechanism of IBC-induced cell death in cancer.
  • To determine if IBC induces non-apoptotic necrosis.
  • To explore the role of reactive oxygen species (ROS) and MPT in IBC-mediated cell death.

Main Methods:

  • Treatment of lung and breast cancer cells with IBC.
  • Assessment of cell death pathways (apoptosis vs. necrosis).
  • Measurement of mitochondrial function, ROS production, and MPT pore opening.
  • Involvement of cyclophilin D (CypD) and ROS scavengers (cyclosporin A, hemin) were tested.
  • Evaluation of IBC's efficacy in a 4T1 breast cancer allograft mouse model.

Main Results:

  • IBC induced non-apoptotic, ROS-mediated necrosis in cancer cells.
  • IBC triggered mitochondrial injury, including Ca2+ overload, MPT pore opening, and membrane potential collapse.
  • ROS scavengers, but not CypD manipulation, reversed IBC-induced cell death.
  • IBC demonstrated anticancer effects in vivo, which were partially reversed by cyclosporin A.

Conclusions:

  • IBC induces non-canonical MPT-driven necrosis via ROS in cancer cells.
  • This mechanism offers a novel therapeutic strategy for cancer treatment.
  • Targeting ROS-mediated necrosis presents a promising avenue for anticancer drug development.
Keywords:
IsobavachalconeMPT-Driven necrosisMitochondriaROS

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