Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism.
Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae which kill drug-sensitive and multidrug-resistant breast cancer cells in culture. Currently, the mechanisms of jadomycin cytotoxicity are poorly understood; however, reactive oxygen species (ROS)-induced DNA cleavage is suggested based on bacterial plasmid DNA cleavage studies. The objective of this study was to determine if and how ROS contribute to jadomycin cytotoxicity in drug-sensitive MCF7 (MCF7-CON) and taxol-resistant MCF7 (MCF7-TXL) breast cancer cells. As determined using an intracellular, fluorescent, ROS-detecting probe, jadomycins B, S, SPhG, and F dose dependently increased intracellular ROS activity 2.5- to 5.9-fold. Cotreatment with the antioxidant N-acetyl cysteine lowered ROS concentrations to below baseline levels and decreased the corresponding cytotoxic potency of the four jadomycins 1.9- to 3.3-fold, confirming a ROS-mediated mechanism. Addition of CuSO4 enhanced, whereas addition of the Cu(II)-chelator d-penicillamine reduced, the ROS generation and cytotoxicity of each jadomycin. Specific inhibitors of the antioxidant enzymes, superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase, but not catalase, enhanced jadomycin-mediated ROS generation and anticancer activity. In conclusion, the results indicate that jadomycin cytotoxicity involves the generation of cytosolic superoxide via a Cu(II)-jadomycin reaction, a mechanism common to all jadomycins tested and observed in MCF7-CON and drug-resistant MCF7-TXL cells. The superoxide dismutase 1, glutathione, and peroxiredoxin/thioredoxin cellular antioxidant enzyme pathways scavenged intracellular ROS generated by jadomycin treatment. Blocking these antioxidant pathways could serve as a strategy to enhance jadomycin cytotoxic potency in drug-sensitive and multidrug-resistant breast cancers.
Department of Pharmacology, Faculty of Medicine, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
Steven R
SR
Hall
College of Pharmacy, Faculty of Health Professions, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
Heather L
HL
Blundon
College of Pharmacy, Faculty of Health Professions, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
Matthew A
MA
Ladda
Department of Chemistry, Faculty of Sciences, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
Andrew W
AW
Robertson
Department of Chemistry, Faculty of Sciences, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
Camilo F
CF
Martinez-Farina
College of Pharmacy, Faculty of Health Professions, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2 ; Department of Chemistry, Faculty of Sciences, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
David L
DL
Jakeman
Department of Pharmacology, Faculty of Medicine, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2 ; College of Pharmacy, Faculty of Health Professions, Dalhousie University Halifax, Nova Scotia, Canada, B3H 4R2.
Kerry B
KB
Goralski
Antioxidants; breast cancer; jadomycins; multidrug resistance; natural products; reactive oxygen species