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- Title
Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells.
- 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.
- Abstract
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 (IC50) 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 G1-phase, suggesting a G1 delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and γH2AX 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 H2DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with N-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.
- Subjects
ARTEMISININ derivatives; CANCER cells; ELECTRON paramagnetic resonance spectroscopy; HYDROGEN peroxide; PANCREATIC cancer; ARTEMISININ
- Publication
Antioxidants, 2020, Vol 9, Issue 2, p108
- ISSN
2076-3921
- Publication type
Article
- DOI
10.3390/antiox9020108