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

Abstract

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.

Mechanism of juglone-induced apoptosis of MCF-7 cells by the mitochondrial pathway

“…In the present study, flow cytometry showed that juglone increased the levels of ROS in MCF-7 cells, in agreement with previous findings (Inbaraj and Chignell, 2004), but that this effect was reduced in the presence of NAC. Increased ROS levels likely interfere with the functioning of the mitochondrial electron transport chain, and decrease mitochondrial transmembrane potential by reducing the oxidation state of the mitochondrial inner membrane and by damaging mitochondrial DNA and several key proteins (Hall et al, 2015).…”

Self assembled arjunolic acid acts as a smart weapon against cancer through TNF- α mediated ROS generation

“…After treatment the cells were washed 3 times with PBS and the DCF fluorescenceintensity was measure under the fluorescence microscope [24].…”

The expansive library of jadomycins

“…At the time of publication, over forty-five of the described jadomycins have been evaluated for biological activity, including various cancer cytotoxicity assays [7][8][9][10]13,15,[17][18][19][20]25,[32][33][34][35] and antimicrobial panels. 6,20,33,34 Jadomycins have been implicated in the inhibition of aurora kinase B 10,54 and topoisomerases.…”

“…2,3 The jadomycins are distinct from the other natural product angucyclines by their inclusion of a nitrogenous heterocycle, 1 which is the result of a non-enzymatic incorporation of an amino acid into the polyaromatic core. 4,5 This non-enzymatic process has permitted the generation of a large library of jadomycins, enabling the determination of structureactivity relationships with respect to the antibiotic 6 and cytotoxic [7][8][9][10] activity of the jadomycins. Jadomycin nomenclature often includes the incorporated amino acid, for instance, jadomycin S (Jd S) refers to the natural product isolated through incorporation of L-serine into the jadomycin.…”