期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 65, 期 -, 页码 305-316出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.07.002
关键词
Selenocystine; 5-Fluorouracil; Chemosensitization; Apoptosis; Synergy; Free radicals
资金
- National Science and Technology [2012BAC07B05]
- Natural Science Foundation of China and Guangdong Province
- Program for New Century Excellent Talents in University
- Doctoral Program of Higher Education of China
- China Postdoctoral Science Foundation
5-Fluorouracil (5-FU)-based chemotherapy as a first-line treatment is quite limited, because of its inefficiency and clinical resistance to it. The search for chemosensitizers that could augment its efficiency and overcome the drug resistance to 5-FU has kindled great interest among scientists. Selenocystine (SeC), a naturally occurring selenoamino acid, displayed broad-spectrum anticancer activity in our previous studies. This study demonstrates that SeC acts as an effective enhancer of 5-FU-induced apoptosis in A375 human melanoma cells through induction of mitochondria-mediated apoptosis with the involvement of DNA damage-mediated p53 phosphorylation and ERK inactivation. Pretreatment of the cells with SeC significantly enhanced 5-FU-induced loss of mitochondrial membrane potential (Delta psi(m)) by regulating the expression levels of Bcl-2 family proteins. SeC and 5-FU in combination also triggered cell oxidative stress through regulation of the intracellular redox system and led to DNA damage and inactivation of ERK and AKT. Moreover, inhibitors of ERK and AKT effectively enhanced the apoptotic cell death induced by the combined treatment. However, pretreatment of the cells with glutathione reversed the apoptosis induced by SeC and 5-FU and recovered the expression of ERK and AKT inactivation, which revealed the important role of reactive oxygen species in cell apoptosis and regulation of ERK and AKT pathways. Taken together, our results suggest that a strategy of using SeC and 5-FU in combination could be a highly efficient way to achieve anticancer synergism. (C) 2013 Elsevier Inc. All rights reserved.
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