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Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism

Steven R Hall1, Heather L Blundon2, Matthew A Ladda2

  • 1Department of Pharmacology, Faculty of Medicine, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.

Pharmacology Research & Perspectives
|March 3, 2015
PubMed

Insights

Jadomycins kill breast cancer cells by increasing reactive oxygen species (ROS). Antioxidant enzymes normally reduce this effect, but blocking them may enhance jadomycin

Area of Science:

  • Natural Products Chemistry
  • Cell Biology
  • Biochemistry

Background:

  • Jadomycins, natural products from *Streptomyces venezuelae*, exhibit cytotoxicity against drug-sensitive and multidrug-resistant breast cancer cells.
  • The precise mechanisms underlying jadomycin cytotoxicity remain unclear, though reactive oxygen species (ROS)-induced DNA cleavage is a proposed pathway.

Purpose of the Study:

  • To investigate the role of ROS in jadomycin-induced cytotoxicity in both drug-sensitive (MCF7-CON) and taxol-resistant (MCF7-TXL) breast cancer cells.
  • To elucidate the specific pathways involved in ROS generation and scavenging during jadomycin treatment.

Main Methods:

  • Quantification of intracellular ROS levels using a fluorescent probe in jadomycin-treated breast cancer cells.
  • Assessment of jadomycin cytotoxicity and ROS generation in the presence of antioxidants (N-acetyl cysteine) and copper ions (CuSO4, d-penicillamine).
  • Evaluation of the impact of specific antioxidant enzyme inhibitors (superoxide dismutase 1, glutathione S-transferase, thioredoxin reductase, catalase) on jadomycin's effects.

Main Results:

  • Jadomycins dose-dependently increased intracellular ROS levels (2.5- to 5.9-fold) in both cell lines.
  • Antioxidant treatment (N-acetyl cysteine) reduced ROS and decreased jadomycin cytotoxicity (1.9- to 3.3-fold), confirming a ROS-mediated mechanism.
  • Copper ions (CuSO4) enhanced ROS generation and cytotoxicity, while chelation (d-penicillamine) reduced these effects. Inhibitors of superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase potentiated jadomycin's anticancer activity.

Conclusions:

  • Jadomycin cytotoxicity is mediated by the generation of cytosolic superoxide through a Cu(II)-jadomycin reaction.
  • Cellular antioxidant pathways, including superoxide dismutase 1, glutathione, and thioredoxin systems, counteract jadomycin-induced ROS.
  • Inhibiting these endogenous antioxidant pathways presents a potential strategy to enhance the efficacy of jadomycins against drug-sensitive and multidrug-resistant breast cancers.
Keywords:
Antioxidantsbreast cancerjadomycinsmultidrug resistancenatural productsreactive oxygen species

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