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Yang J, Li H, Chen YY, Wang XJ, Shi GY, Hu QS, Kang XL, Lu Y, Tang XM, Guo QS, Yi J: Anthraquinones sensitize tumor cells to arsenic cytotoxicity in vitro and in vivo via reactive oxygen species-mediated dual regulation of apoptosis. Free Radic Biol Med. 2004 Dec 15;37(12):2027-41.
Cellular oxidation/reduction state affects the cytotoxicity of a number of chemotherapeutic agents, including arsenic trioxide. Reactive oxygen species (ROS), the major intracellular oxidants, may be a determinant of cellular susceptibility to arsenic. Our previous studies showed that a naphthoquinone and an anthraquinone (emodin) displayed the capability of producing ROS and facilitating arsenic cytotoxicity in both leukemia and solid tumor cell lines. We therefore attempted to test emodin and several other kinds of anthraquinone derivatives on EC/CUHK1, a cell line derived from esophageal carcinoma, and on a nude mouse model, with regard to their effects and mechanisms. Results showed that anthraquinones could produce ROS and sensitize tumor cells to arsenic both in vivo and in vitro. The combination of emodin and arsenic promoted the major apoptotic signaling events, i.e., the collapse of the mitochondrial transmembrane potential, the release of cytochrome c, and the activation of caspases 9 and 3. Meanwhile a combination of emodin and arsenic suppressed the activation of transcription factor NF-kappaB and downregulated the expression of a NF-kappaB-specific antiapoptotic protein, survivin. These two aspects could be antagonized by the antioxidant N-acetyl-L-cysteine. Therefore anthraquinones exert their effects via a ROS-mediated dual regulation, i.e., the enhancement of proapoptosis and the simultaneous inhibition of antiapoptosis. In vivo study showed that emodin made the EC/CUHK1 cell-derived tumors more sensitive to arsenic trioxide with no additional systemic toxicity and side effects. Taken together, these results suggest an innovative and safe chemotherapeutic strategy that uses natural anthraquinone derivatives as ROS generators to increase the susceptibility of tumor cells to cytotoxic therapeutic agents. |
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