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Mechanism of neem limonoids-induced cell death in cancer: Role of oxidative phosphorylation

Neelu Yadav1, Sandeep Kumar1, Rahul Kumar1

  • 1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Free Radical Biology & Medicine
|December 3, 2015
PubMed

Insights

Neem limonoids induce cancer cell death by targeting the oxidative phosphorylation (OXPHOS) system. This process involves increased reactive oxygen species (ROS) and mitochondrial biomass, independent of proapoptotic Bcl-2 family proteins.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Neem limonoids have demonstrated potential in inducing cancer cell death through various pathways.
  • Understanding the precise mechanisms of neem-induced apoptosis is crucial for therapeutic development.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying neem limonoid-induced apoptotic cell death in cancer.
  • To investigate the role of mitochondrial function and oxidative phosphorylation (OXPHOS) in neem-induced apoptosis.

Main Methods:

  • Assessing caspase activation, mitochondrial outer membrane permeabilization, and mitochondrial morphology.
  • Measuring mitochondrial DNA and biomass, and evaluating the activity of OXPHOS complexes.
  • Investigating the impact of deficiencies in specific OXPHOS components (Complex-I, Complex-II) on neem-induced cell death.
  • Analyzing reactive oxygen species (ROS) levels and their correlation with apoptosis.

Main Results:

  • Neem-induced caspase activation does not rely on classical mitochondrial outer membrane permeabilization pathways.
  • Neem exposure increased mitochondrial DNA, biomass, and reactive oxygen species (ROS) levels.
  • Complex-I deficiency partially inhibited, while Complex-II deficiency significantly reduced, neem-induced apoptosis.
  • Ablation of multiple OXPHOS complexes did not inhibit caspase activation, suggesting a complex interplay.

Conclusions:

  • Neem limonoids induce cancer cell death by specifically targeting the oxidative phosphorylation (OXPHOS) system.
  • The mechanism involves ROS generation and modulation of OXPHOS complexes, independent of proapoptotic Bcl-2 family proteins.
Keywords:
ApoptosisMitochondrial DNANecroptosisNeemOxidative phosphorylation complexROS

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