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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase

Rafal R Nazarewicz1, Woineshet J Zenebe, Arti Parihar

  • 1Vascular Surgery, Davis Heart and Lung Research Institute, and Institute of Mitochondrial Biology, Ohio State University Medical Center, 473 West 12th Avenue, Columbus, OH 43210, USA.

Cancer Research
|February 7, 2007
PubMed

Insights

Tamoxifen, an anticancer drug, triggers apoptosis by increasing mitochondrial calcium and stimulating mitochondrial nitric oxide synthase (mtNOS). This mtNOS activation disrupts cellular respiration and promotes cell death in cancer cells.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Tamoxifen is a widely used anticancer drug.
  • Tamoxifen induces apoptosis through oxidative stress and nitric oxide (NO)-dependent pathways.
  • Mitochondria play a crucial role in tamoxifen-induced apoptosis.

Purpose of the Study:

  • To investigate the role of mitochondrial nitric oxide synthase (mtNOS) in tamoxifen-induced apoptosis.
  • To examine the effect of tamoxifen on intramitochondrial calcium levels and mtNOS activity.
  • To elucidate the downstream mechanisms linking mtNOS activation to apoptosis.

Main Methods:

  • Experiments were conducted using mitochondria isolated from rat liver and human breast cancer MCF-7 cells.
  • Measurements included intramitochondrial ionized Ca(2+) concentration and mtNOS activity.
  • Assessed mitochondrial respiration, cytochrome c release, lipid peroxidation, protein tyrosine nitration, and enzyme activity.

Main Results:

  • Tamoxifen increased intramitochondrial ionized Ca(2+) concentration.
  • Tamoxifen stimulated mtNOS activity in isolated mitochondria.
  • mtNOS stimulation led to impaired mitochondrial respiration, cytochrome c release, increased lipid peroxidation, protein nitration, decreased succinyl-CoA:3-oxoacid CoA-transferase activity, and mitochondrial aggregation.

Conclusions:

  • Mitochondrial NO synthase plays a critical role in tamoxifen-induced apoptosis.
  • Tamoxifen's apoptotic effects are mediated, in part, by the activation of mtNOS.
  • Targeting mtNOS could be a potential therapeutic strategy in tamoxifen treatment.

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