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

Pharmacology Research & Perspectives
Steven R HallKerry B Goralski

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 catalas...Continue Reading

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Citations

Dec 19, 2015·Oxidative Medicine and Cellular Longevity·Nuria Mut-SaludFernando Rodríguez-Serrano
Sep 15, 2017·The Journal of Pharmacology and Experimental Therapeutics·Steven R HallKerry B Goralski
Jun 9, 2021·Journal of Industrial Microbiology & Biotechnology·Juan Pablo Gomez-EscribanoMervyn J Bibb
Aug 10, 2021·Archives of Microbiology·Zainab AbdelghaniRouba Hage-Sleiman
Oct 29, 2021·Pharmacology Research & Perspectives·Esther P BonittoKerry B Goralski

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