Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells.
Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC(50)=15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.
Johns Hopkins University, School of Medicine, Department of Internal Medicine, Division of Hematology, 720 Rutland Avenue, Baltimore, MD 21205, USA. aemadi1@jhmi.edu
Ashkan
A
Emadi
Anne
A
Le
Cynthia J
CJ
Harwood
Kenneth W
KW
Stagliano
Farin
F
Kamangar
Ashley E
AE
Ross
Charles R
CR
Cooper
Chi V
CV
Dang
Judith E
JE
Karp
Milena
M
Vuica-Ross
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D009285:Naphthoquinones; D017382:Reactive Oxygen Species