Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4‐d]pyrimidine nucleoside derivatives‐induced cancer cell death |
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Authors: | Hai‐liang Liu Jing‐jing Xu Xiao‐min Dai Jing‐Bo Shi Song Xu Jing Gao Qi‐zheng Yao Feng Liu |
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Affiliation: | 1. School of Pharmacy, Jiangsu University, Zhenjiang 212013, People's Republic of China;2. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China;3. Chao Family Comprehensive Cancer Center, University of California Irvine Medical School, Orange, CA 92868, USA |
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Abstract: | Eight novel oxdiazolo[3,4‐d]pyrimidine nucleoside derivatives (I‐VIII) were synthesized to investigate their anti‐tumor effects and possible mechanisms. Four human cancer cell lines including Hela, ECA109, HepG2 and A459 cells were used. Compounds VI and VIII showed significant inhibition on cancer cell proliferation by MTT assay and IC50 values were around 30–70 µmol l?1. Both compounds could release nitric oxide (NO), led to a significant intracellular free Ca2+ overloading and resulted in mitochondrial dysfunction, showing a decrease in mitochondrial membrane potential in HepG2 cells in a dose‐dependent manner. Furthermore, compound VIII induced obvious DNA damage on HepG2 cells. These data indicate that compounds VI and VIII are two active antitumor compounds, and both DNA damage and mitochondrial dysfunction are involved in the mechanisms underlying oxadiazolo[3,4‐d]pyrimidine nucleoside derivative‐induced cancer cell death, which might also be related to the released NO. Copyright © 2009 John Wiley & Sons, Ltd. |
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Keywords: | oxadiazolo[3,4‐d]pyrimidine nucleoside antitumor nitric oxide mitochondrion calcium ion DNA damage |
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