Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells

• Published in: Antioxidants Vol. 9; no. 2; p. 108
• Main Authors: Kalen, Amanda L, Wagner, Brett A, Sarsour, Ehab H, Kumar, Maneesh G, Reedy, Jessica L, Buettner, Garry R, Barua, Nabin C, Goswami, Prabhat C
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.01.2020; MDPI
• Subjects: aliphatic nitro chemistry; artemisinin; Cancer cells; carba-dimer; cyclin d1; Dimer acids; Health aspects; Hydrogen peroxide; oxidative stress; United States; artemisinin; carba-dimer; cyclin D1; aliphatic nitro chemistry; oxidative stress
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox9020108

This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer cells compared to normal human fibroblasts. Compared to artemisinin, AG-1 is more toxic to human breast, prostate, head-neck, pancreas and skin cancer cells; 50% inhibition (IC ) 123 µM in AG-1 vs. 290 µM in artemisinin-treated breast cancer cells. AG-1 treatment decreased (~ 5 folds) cyclin D1 protein expression that correlated with an increase in the percentage of cells in the G -phase, suggesting a G delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and H2AX protein levels. Results from electron paramagnetic resonance spectroscopy showed Fe-catalyzed formation of AG-1 carbon-centered radicals in a cell-free system. Flow cytometry analysis of H DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with -acetyl-l-cysteine and antioxidant enzymes (superoxide dismutase and catalase) significantly suppressed AG-1-induced toxicity, suggesting that superoxide and hydrogen peroxide contribute to AG-1-induced toxicity in human cancer cells. AG-1 represents a novel class of anti-cancer drug that is more potent than its parent compound, artemisinin.